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Journal of Cardiology 64(2014)7074Contents lists available at ScienceDirectJournal of Cardiologyjournal homepage: articleThe clinical usefulness of carotid ultrasonography in patients with aninconclusive exercise treadmill stress test resultCan Yucel Karabay(MD),Gonenc Kocabay(MD),Ahmet Guler(MD),Arzu Kalayci(MD),Taylan Akgun(MD),Cevat Kirma(MD)Kartal Kosuyolu Heart and Research Hospital,Cardiology Department,Istanbul,Turkeya r t i c l ei n f oArticle history:Received 29 June 2013Received in revised form 4 October 2013Accepted 25 October 2013Available online 20 December 2013Keywords:Exercise treadmill testInconclusive resultCarotid intima-media thicknessMyocardial perfusion imaging studya b s t r a c tBackground:Although a treadmill exercise stress testing(EST)is often the first-line screening procedurefor subjects with an intermediate probability of coronary artery disease(CAD),one limitation of this testis the high rate of inconclusive tests that result from borderline exercise-induced ST changes.The carotidintima media thickness(CIMT)correlates well with atherosclerosis.The purpose of this study was toevaluate the clinical usefulness of performing CIMT measurements in patients with an inconclusive EST.Methods:Symptomatic patients without history of vascular disease and with inconclusive EST resultwere included.Inconclusive results were defined as the presence of horizontal or downsloping ST-segment depression between 0.5 and 0.9mm or 1.0 and 1.4mm upsloping ST-segment depression.Afterinconclusive EST regarding electrocardiographic changes,the measurements of the CIMT and myocardialperfusion imaging study(MPS)were performed in all patients.The CIMT was measured at the posteriorwallofthecommoncarotidartery.ThediagnosisofCADwasbasedonthepresenceofreversibleperfusiondefects on exercise MPS.Results:A total of 87 patients(57 men)with a mean age of 58.97.2 years were enrolled.The MPS waspositive in 18 patients.The CIMT in patients with positive MPS was significantly greater than in patientswith negative MPS.The CIMT was 0.820.33mm in patients with positive MPS and 0.630.21mm inpatients with negative MPS(p=0.004).Receiver operating characteristic curve analyses revealed thatthe greatest specificity was obtained when the cut-off value of CIMT was set at 0.66mm(sensitivity 39%;specificity 72.5%;positive predictive value 27%;negative predictive value 82%).Conclusion:In patients with inconclusive electrocardiographic changes during EST,CIMT was a usefulmeasurementtopreventalternativemoreexpensiveandinvasivetests.Additionally,meanCIMTisusefulfor screening patients with an inconclusive EST result to exclude CAD.2013 Japanese College of Cardiology.Published by Elsevier Ltd.All rights reserved.IntroductionExercise treadmill stress testing(EST)is a useful diagnostic toolfor primary assessment of symptomatic patients with an inter-mediate probability of coronary artery disease(CAD)based onclinical findings 1.However,one limitation is the high rate ofnondiagnostic tests.EST results have been classified as negative(no evidence of reversible ischemia),positive(moderately orseverely abnormal),or equivocal(reported as nondiagnostic,sub-optimal,equivocal,possiblyartifactualorminimallyabnormal)2.While the most determined reason for the high rate of nondiagnos-tic tests that result from patients failure to reach the target heartrate,anotherreasonresultsfrominconclusiveelectrocardiographicCorrespondingauthorat:DepartmentofCardiac,ThoracicandVascularSciences,University of Padua,Centro Gallucci,Via Giustiniani 2,35128 Padua,Italy.Tel.:[phone];fax:[phone].E-mail address:(G.Kocabay).abnormalities.In case of nondiagnostic EST,patients are referredfor more expensive and invasive stress tests and consequently,itcauses prolonged hospital evaluation 3.Carotid intima media thickness(CIMT)measurement has beenused as a surrogate index of atherosclerosis.Several studies havefound an association between increased CIMT and the incidenceof cardiovascular disease in the general population 47.Exercisetesting and arterial ultrasonography are able to improve signifi-cantly the accuracy of the risk stratification over conventional riskfactors 8.The purpose of this study was to evaluate the clinical usefulnessofperformingCIMTmeasurementsinpatientswithaninconclusivestress test.MethodsPatient populationThe study population consisted of patients referred to an outpa-tient clinic with stable chest pain and suspected CAD.The sample0914-5087/$see front matter 2013 Japanese College of Cardiology.Published by Elsevier Ltd.All rights reserved.http:/dx.doi.org/10.1016/j.jjcc.2013.10.017C.Y.Karabay et al./Journal of Cardiology 64(2014)707471comprised 87(57 male,mean age 58.97.2 years)consecutivesymptomaticpatientswithnoprevioushistoryofovertatheroscle-rotic disease(cerebral,peripheral,or CAD,which was defined asany degree of CAD on previous angiogram or history of myocar-dial infarction or angina)who underwent exercise test with aninconclusive result.Age ranged from 36 to 74 years.Acompletehistorywastakenandaphysicalexaminationmea-surementofweight,height,bodymassindex(BMI)andsystolicanddiastolicbloodpressureinthesupinepositionafter10minrestand12-lead electrocardiography(ECG)at rest were performed.Bloodsamples were taken for fasting blood glucose and cholesterol level.After the medical examination,patients with an intermediatepretest probability of CAD on the basis of gender,age,and symp-toms(nonangina,atypical angina,or typical angina)were preparedfor treadmill exercise stress testing(EST)for evaluation of symp-toms of possible coronary artery disease 9.Patients with a history of stroke,unstable angina pectoris,myocardial infarction,peripheral artery disease,valvular disease,arrhythmia,abnormal ECGs that would preclude adequate inter-pretation of changes or taking digoxin were excluded.Patientswere excluded if they were pregnant or lactating women.Since theextentofCADmaybeunderestimatedwhencalciumchannelblock-ers and?blockers are given,these medications were discontinuedfor 48h.Informed consent was obtained from each patient.The studyprotocol was approved by the ethical committee of the hospital.Treadmill exercise stress testingEST was performed using a modified Bruce protocol exercisetreadmill test.The protocol for EST has been previously reported9,10.Briefly,modified Bruce protocol was employed.Since ourinstitution uses a heart rate of at least 85%of the adjustedage-predicted maximal heart rate(220beats/min-age)to indicateadequatestress,thepatientswereencouragedtocontinueuntil85%of maximal heart rate was achieved.All participants reached this85%target.Duringexercise,a12-leadECGandbloodpressurewererecorded at the end of each 3-min stage and at peak exercise.Pos-texercise ECGs were obtained after 5min.Based on clinical or ECGresponse,the test was considered as normal(negative),ischemic(positive),and inconclusive.The EST was considered ischemic if there was horizontal ordownsloping ST-segment depression of at least 1.0mm or 1.5mmupsloping ST-segment depression,80ms after the J point in1 lead was observed.However,in the presence of horizontal ordownsloping ST-segment depression from 0.5 to 0.9mm or 1.0 to1.4mm upsloping ST-segment depression,the test was consideredas inconclusive.Patients with inconclusive ECG findings wereassessed.Besides the ECG findings,blood pressure response to exercise isan important finding.Hypertensive blood pressure response wasdefined as systolic blood pressure of 220mmHg and/or a diastolicblood pressure of 95mmHg.Myocardial perfusion imaging studyEighty-seven subjects with an inconclusivetreadmill EST werereferred for exercise myocardial perfusion single-photon emis-sion tomography(SPECT)imaging.Studies were performed usingthe treadmill(Series 2000 Treadmill;GE Marquette Medical Sys-tems,Milwaukee,WI,USA)according to a Bruce protocol.Theisotope used was 99 mTc(technetium)-sestamibi.At 1min beforepeak exercise,the stress dose of sestamibi was injected intra-venously.The patient exercised for at least 1min longer after theinjection.Stress and rest studies were performed using a 1-dayprotocol“one-day rest/stress Tc-99m protocols”for exercise stressaccording to the consensus report 11.Resting and peak exercise99mTc sestamibi injection with perfusion imaging was performedusing a gamma camera(Infia;H300WE,VC GE Medical System,Tirat Hacarmel,Israel).A positive test was defined as the presenceof one or more reversible perfusion defects during stress.Measurement of carotid intima-media thicknessAllcarotidultrasonographicexaminationswereperformedwiththe same device(Logic S8;GE Medical Systems)equipped with an8-MHz linear probe.Patients were examined in the supine positionwith the head 45away from the side being scanned.Digital images were stored directly from the ultrasound system.Far-wall CIMTs were measured in the distal of each carotid arteryin the proximal 1cm of carotid bulb in areas free of plaque usingB-mode imaging 12.Measurements were repeated three timesand results were averaged.Mean CIMT values from the far walls ofthe right and left common carotid arteries were reported.Plaquewas defined as focal wall being 50%thicker than the surroundingwall.Presence of any calcification,plaque,and echocardiographi-cally lucent components was noted.Statistical analysisCategorical and numeric variables are expressed in percentageand meanstandard deviations respectively.Numerical variableswere tested with MannWhitney U-test,and categorical variableswere tested using Fishers exact test or Chi-square test whicheverwas suitable.Spearmans test was used for correlation analysis.Sensitivity and specificity values for positive MPS were calculatedfrom receiver operating characteristic curve(ROC).A p-value of0.05 was regarded significant for all analyses.All the statisticaltests were done using SPSS 11.5(SPSS Inc.,Chicago,IL,USA).ReproducibilityIntra-and interobserver reproducibilities were assessed forCIMT values.For intraobserver variability,the same operatorperformed a second measurement more than a month afterthe initial analysis.The BlandAltman analysis for interobserverreproducibility mean difference95%confidence interval(CI)andintraobserverreproducibilityintraclasscorrelationcoefficient(ICC),95%CI were calculated.The interobserver and intraobserverreproducibilityshowedaperfectagreementfortheCIMTinterob-server and intraobserver agreement were assessed as 0.04(0.09to 0.11)and(0.92),(0.890.94),respectively.ResultsA total of 87 patients(males,65.5%)with a mean age of 58.9(7.2)years who had an intermediate pretest probability(1090%)of CAD based on age,gender,and nature of symptoms wereincluded.Among them,59 patients had hypertension,25 dysli-pidemia,55 were smokers,and 21 had diabetes mellitus.Baselinecharacteristics of the study population are shown in Table 1.After inconclusive EST regarding ECG changes,the measure-mentsofCIMTandmyocardialperfusionimagingstudy(MPS)wereperformed in all patients.All ultrasound examinations(100%)provided images goodenough to allow the measurement of the CIMT.We did notobserve any calcification or plaque.Mean CIMT was found to be0.670.25mm.Coronary artery disease was diagnosed based on the MPS.TheMPS was positive in 18(21%)of the 87 patients.Patients withpathologicresultsoftheperfusionstudyhadaborderlinedifferencein levels of low-density lipoprotein cholesterol and age(for both,72C.Y.Karabay et al./Journal of Cardiology 64(2014)7074Table 1Baseline characteristics of patients.n=87Number(%)MeanSDAge(years)58.9(3674)7.2Men57(65.5)Height166.59.3Weight73.710.4Body mass index(kg/m2)26.51.8Hypertension59(67.8)Dyslipidemia25(28.7)Diabetes mellitus21(24.1)Smokers55(63.3)Family history ofpremature coronarydisease32(36.8)Medication useStatins25(28.7)?blockers17(19.5)Angiotensin inhibitors46(52.9)Calcium channel blockers28(32.2)Heart rate69.58.9Systolic BP145.520Diastolic BP76.812.4Mean CIMT(mm)0.670.25Values are meansSD or numbers of patients(percentages).BP,blood pressure;CIMT,carotid intimal-media thickness;SD,standard deviation.p=0.05)(Table 2).The MPS-positive patients had a higher bloodpressure response(p=0.001).The CIMT in patients with positiveMPS was significantly greater than in patients with negative MPS.The CIMT was 0.820.33mm in patients with positive MPS and0.630.21mm in patients with negative MPS(p=0.004)(Fig.1).By Spearman correlation analysis,there was a significant mod-erate correlation between CIMT and level of total cholesterol,systolic blood pressure,and advanced age(for all,p0.001)(Table 3).In order to determine cut-off value of CIMT for the predictionabilityofpositiveMPS,ROCcurveswereplottedformeanCIMT.Theanalysisshowedthatthegreatestspecificitywasobtainedwhenthecut-offvalueofCIMTwassetat0.66mm(sensitivity39%;specificityTable 2Characteristics of myocardial perfusion imaging study(MPS)positive and negativepatients.MPS(+)n=18MPS()n=69p-ValueAge(years)61.87.358.270.05Men9(50)48(69)0.12Height168.710.61668.90.27Weight75.710.573.2100.35Body mass index(kg/m2)26.50.8226.41.950.92Hypertension15(83.3)44(63.7)0.11Systolic BP151.418.214420.10.16Diastolic BP76.611.676.912.70.92Heart rate71.19.469.18.80.39Diabetes mellitus5(28)16(25)0.69Total cholesterol(mg/dl)2417 9218600.19LDL-cholesterol(mg/dl)148.235.312936.80.05HDL-cholesterol(mg/dl)39.816.83611.30.37Family history ofpremature coronarydisease4(22.2)28(41)0.15Smokers13(72)42(61)0.37Type of ST-segmentchanges(%)-(I/II/III)61/22/1761/29/100.68Hypertensive BP response12(67)15(22)0.001Mean CIMT(mm)0.820.330.630.210.004Values are number(%).BP,blood pressure;CIMT,carotid intimal-media thickness;LDL,low-density lipoprotein;HDL,high-density lipoprotein.Type of ST-segment changes I/II/III represent upslope,horizontal,downslope,respectively.Fig.1.Distribution of the intima-media thickness in myocardial perfusion imagingstudy positive and negative patients.MPS,myocardial perfusion imaging study;CIMT,carotid intima media thickness.Table 3The correlation analysis of carotid intima-media thickness and risk factors.CIMTrpTotal cholesterol0.4150.001Systolic BP0.4060.001Age0.4300.001BP,blood pressure;CIMT,carotid intimal-media thickness.72.5%;positivepredictivevalue27%;negativepredictivevalue82%)(Fig.2).In the setting of an inconclusive EST result,presence ofCIMT0.66mm predicted the absence of perfusion defects(con-sequently CAD)diagnosed by MPS(negative predictive value 82%).Fig.2.Receiver operating characteristic(ROC)curve analysis to identify positivemyocardialperfusionimagingstudy.Thecut-offvalueofmeancarotidintima-mediathickness was set at 0.66mm.C.Y.Karabay et al./Journal of Cardiology 64(2014)707473NospecificECGchangesintheESTwerefoundtopredicttheout-come of the MPS.However,hypertensive blood pressure responsewas more prevalent in subjects with a pathologic perfusion study.DiscussionIn this study,we prospectively examined the predictive valueof CIMT for the presence of perfusion defects diagnosed by MPS insymptomatic patients after inconclusive EST.The CIMT in the present stud