Carotid and femoral arterial wall changes and the prevalence of clinical cardiovascular disease

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1 Carotid ad femoral arterial wall chages ad the prevalece of cliical cardiovascular disease Maura Griffi Vascular Noivasive Screeig ad Diagostic Cetre, Adrew Nicolaides The Cyprus Istitute of Neurology ad Geetics; Departmet of Biological Scieces, Uiversity of Cyprus; Departmet of Vascular Surgery, Imperial College; Vascular Screeig ad Diagostic Cetre, Cyprus, Theodosis Tyllis The Cyprus Istitute of Neurology ad Geetics; Vascular Screeig ad Diagostic Cetre, Cyprus, Niki Georgiou The Cyprus Istitute of Neurology ad Geetics; Vascular Screeig ad Diagostic Cetre, Cyprus, Richard M Marti MRC Cetre for Causal Aalysis i Traslatioal Epidemiology, Departmet of Social Medicie, Uiversity of Bristol, Daw Bod Vascular Noivasive Screeig ad Diagostic Cetre, Adrie Paayiotou Departmet of Biological Scieces, Uiversity of Cyprus, Chrysa Tziakouri Departmet of Radiology, Nicosia Geeral Hospital, Carolie J Doré MRC Cliical Trials Uit ad Charris Fessas The Cyprus Heart Foudatio Abstract: The Cyprus Study is a prospective cohort study of cardiovascular disease (CVD). Its aim is to determie the relatioship of itima media thickess (IMT) of the commo carotid (IMTcc), maximum thickess of IMT i the carotid bifurcatio (IMTmax), umber of carotid ad femoral bifurcatios with plaque ad total plaque thickess (TPT) (sum of the maximum plaque measuremets take from the four bifurcatios scaed) with the prevalece of cliical CVD. A total of 767 idividuals (46% male) over the age of 40 years were recruited from a moutai village ad a tow outside the capital Nicosia. I additio to cliical examiatio, carotid ad commo femoral bifurcatios were scaed with ultrasoud. After cotrollig for covetioal risk factors, there was little evidece of a associatio of IMTcc with CVD prevalece. However, IMTmax ad TPT were associated with 2.9-fold (1.22 to 7.07) ad 6.87-fold (2.42 to 19.43) icreased odds of CVD prevalece, respectively. I coclusio, the TPT ad umber of bifurcatios with plaque are more strogly associated with the prevalece of CVD. These fidigs warrat ivestigatio i prospective studies to documet associatios with icidet CVD evets. Keywords: arterial wall, atherosclerosis, ultrasoic imagig Itroductio Carotid itima media thickess (IMT) 1 3 ad the presece ad umber of carotid plaques 4 7 are surrogate markers of atherosclerosis. They have bee associated with the extet ad severity of coroary atherosclerosis 8,9 ad future episodes of myocardial ifarctio ad stroke. 1 4,6,7 Measuremets of IMT vary. Some authors obtai IMT measuremets i the distal commo carotid artery (IMTcc) where plaques rarely occur. 2,4,7 Others measure IMT at several sites of the carotid bifurcatio (IMTbif), icludig both the carotid bulb ad the iteral carotid artery, 1,3,8 obtaiig the mea 1,8 or maximum 3 thickess at these sites. These IMTbif measuremets iclude the thickess Correspodig author: MB Griffi, Vascular Screeig ad Diagostic Cetre, 28 Weymouth Street, Lodo W1G 7BZ, Uited Kigdom. maurabgriffi@googl .com of plaques wheever plaques were preset. IMTcc ad IMTbif have bee associated with differet risk factors ad prevalece of cardiovascular disease (CVD). 5 Irrespective of IMT measuremets, the presece ad umber of plaques, however small, are thought to be good predictors of future cardiovascular evets 5 ad strokes. 6 More recetly, other ultrasoud markers of atherosclerotic CVD have bee idetified: the combiatio of the maximum IMTcc with the maximum IMT i the iteral carotid artery provides a better predictio of the risk for stroke tha IMTcc o its ow; 7 carotid plaque area ad plaque volume have bee show to be associated with icreased cardiovascular risk; ad the presece of femoral plaques is thought to be a marker of coroary artery disease. 13,14 Subcliical CVD is a importat predictor of subsequet coroary heart disease ad stroke eve after cotrollig for covetioal risk factors, suggestig that better use of subcliical measuremets The Author(s), Reprits ad permissios: / X

2 228 M Griffi et al. (such as ultrasoic arterial wall measuremets) could improve our ability to stratify patiets ito those at icreased risk of CVD. 15 Studies comparig the associatio betwee differet ultrasoic measuremets ad cardiovascular disease 5,6 suggest that the presece of plaques whose thickess is ofte icluded i IMT measuremets may be a better predictor of cardiovascular evets tha IMTcc, which was foud to add little to the predictive power of covetioal easily obtaiable risk factors. 16 The aim of the preset study was to determie the relatioship of IMTcc, maximum carotid IMTbif (IMTmax), the presece of carotid ad commo femoral plaques, the umber of bifurcatios with plaque ad the size of plaques i both carotid ad commo femoral bifurcatios (total plaque thickess, TPT) with the prevalece of CVD i a ogoig cross-sectioal populatio-based study. Methods The Cyprus Study is a prospective cohort study of cardiovascular disease i 2000 idividuals aged 40 years or more. Part I cosists of a pilot study of 500 idividuals; part II is curretly i progress ad aims to exted this to 2000 idividuals; ad part III will provide a miimum of 5 years of follow-up. The material preseted i this paper is based o the first 767 idividuals recruited. Baselie data have bee collected from Pedoulas, a village i the Troodos Moutais of Cyprus ( = 271), their relatives who live i ay oe of the mai tows ( = 250) ad from a sectio of Nissou, a village i the Mesaoria plai 10 km south of the capital, Nicosia ( = 246). These sites were radomly selected by havig a blidfolded perso throw darts at a map of Cyprus. All ihabitats were idetified through the populatio list held at the Mayor s office ad all those over the age of 40 years were ivited to participate. This was doe by settig up a ope public meetig as arraged through the district s Mayor ad Local Coucil Committee ad the local Greek Orthodox Priest. The reasos for the study ad the eed for the audiece s participatio were carefully explaied, with a ope questio-ad-aswer debate at the ed. The whole team ivolved i the study were preset ad the evet was kept as iformal as possible. As a result the overall participatio rate of those ivited was 95%. The Ethics Committee of the Cyprus Istitute of Neurology ad Geetics approved the study. All participats provided writte iformed coset. A full medical history was take ad a physical examiatio was made with emphasis o covetioal cardiovascular risk factors ad cardiovascular symptoms icludig agia, myocardial ifarctio, ischemic hemispheric eurological evets ad itermittet claudicatio. All past ad curret medicatios were recorded as well as height ad weight measuremets ad a sittig blood pressure, measured three times with the first measuremet beig discarded. A restig 12-lead ECG was obtaied. A fastig (8 12 hours) blood sample was obtaied for serum total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides ad glucose estimatios. Diabetes was cosidered preset if participats were takig oral hypoglycemic agets, isuli or had a fastig blood sugar i excess of 7.0 mmol/l. The diagosis of agia was based o the history take ad o cofirmatory hospital ivestigatios, icludig ECG or thallium stress test; that of myocardial ifarctio was based o history ad o hospital documetatio, icludig iformatio o coroary artery itervetio (agioplasty or coroary artery bypass). ECGs were reported cetrally by a cardiologist (CF) ad a vascular iterist (TT). Myocardial ischemia was diagosed i the presece of ST-segmet depressio or symmetrical T-wave iversio. ST-segmet depressio was cosidered preset if it was horizotal or dow-slopig ad at least 0.05 mv. Iverted T-wave was cosidered preset if it was isoelectric, egative or biphasic i leads V3 V6, avl (if R > 0.5 mv), I ad II. At least a 0.1 mv T-wave iversio was required i leads V2 ad avf (positive QRS also required). A old myocardial ifarct was diagosed i the presece of a pathological Q-wave: amplitude greater tha 0.1 mv with Q/R ratio greater tha 0.33 ad duratio greater tha 0.04 s or whe QS patters were preset i precordial leads. The diagosis of ischemic stroke, trasiet ischemic attack (TIA) or trasiet moocular blidess was based o the patiet s history, hospital records, ad reports from eurologists who saw the patiet at the time of the evet. Itermittet claudicatio was diagosed from the history of recurret pai o walkig at a fixed distace i the presece of weak or abset pulses ad a akle/brachial blood pressure idex less tha 0.9. All scas were performed usig a Philips (ATL) HDI 5000 duplex scaer (Seattle, WA, USA). A broadbad width liear array trasducer MHz was used. Techical ultrasoud parameters were preset, so that the settigs 2-D map (map 1), post-processig curve (liear), dyamic rage (170 db), persistece (low) ad frame rate (high) remaied costat. Each carotid bifurcatio was examied trasversely first, ad the logitudially to esure optimal demostratio of the itima media complex of both the ear ad far walls of the commo carotid artery cm proximal to the carotid bulb. All participats were examied i the supie positio with the eck slightly exteded. The IMT complex

3 Arterial wall chages ad cardiovascular disease 229 of the far wall of the artery was measured at its thickest part (mea of three readigs). The mea of the measuremets from both carotid arteries was used i the aalysis (IMTcc). A arterial bifurcatio (iteral carotid or commo femoral bifurcatio) was classified as beig affected by plaque if there was a focal thickeig of greater tha 1.2 mm that did ot uiformly ivolve the whole arterial wall. 5 Careful trasverse ad logitudial scaig with the use of colour flow allowed better appreciatio of the geometry ad borders of the plaque, thereby allowig a more accurate assessmet ad measuremet of plaque thickess. The maximum plaque thickess (IMTmax) i both logitudial ad trasverse sectios was measured. I the absece of plaques the IMTcc measuremet was used. The mea of the measuremets from both carotid arteries was used i the aalysis. Both the commo femoral artery bifurcatios were also examied ad if plaques were preset the maximum plaque thickess, as assessed o both logitudial ad trasverse sectios, was measured. The TPT was defied as the sum of the maximum plaque measuremets made i each of the four bifurcatios scaed. The whole examiatio was recorded o VHS videotape ad images with the measuremets were also stored o mageto-optical discs (230 MB rewritable). Reproducibility Two ultrasoographers repeated measuremets i 35 participats. The iter-observer mea differece betwee repeat measuremets of IMTcc were 0.03 mm, the withi-subject stadard deviatio was 0.12 mm ad the itra-class correlatio coefficiet was For IMTmax, which icluded plaque thickess, the correspodig values were 0.02 cm, 0.26 cm ad Data aalysis The distributios of IMTcc, IMTmax ad TPT were divided ito quartiles. The associatios betwee these ultrasoic measuremets ad prevalet cardiovascular disease were ivestigated by calculatig the odds ratio for CVD comparig each of the 2d, 3rd ad 4th quartiles with the 1st quartile (lowest values). Aalyses were udertake both without (crude model) ad with adjustmet for covetioal risk factors. Associatios betwee the umber of carotid ad femoral bifurcatios with plaque (i total ad separately for the carotid ad femoral arteries) ad cardiovascular disease were ivestigated by computig crude ad multivariable adjusted (for covetioal risk factors) odds ratios. The cut-off poit for TPT (cotiuous variable with the highest adjusted odds ratios) with the highest combied sesitivity ad specificity was idetified from the receiver operator characteristics (ROC) curve. Its diagostic ability for the presece of CVD i the populatio was determied i terms of sesitivity, specificity, positive ad egative predictive values ad the likelihood ratio for a positive test result. Statistical aalyses were computed usig SPSS software versio 10.0 (SPSS Ic.). Results Of the 767 idividuals studied, 113 (14.7%) had cliical evidece of CVD. This was primarily because of a documeted myocardial ifarctio with hospital admissio ad/or presece of ifarct o ECG i 58, presece of agia ad/or myocardial ischemia o ECG i 43, ischemic hemispheric eurological evets i ie (five strokes, four TIAs) ad lower limb ischemia i three. IMTcc was ormally distributed, but IMTmax ad TPT were positively skewed. The umber of bifurcatios with plaque was zero i 214, oe i 145, two i 174, three i 96 ad four i 138 of the 767 idividuals studied. The baselie characteristics of the populatio studied are show i Table 1. Table 1 Overall baselie characteristics of the populatio ( = 767) 5.75 ± 1.06 Age, years, mea ± SD a 60.5 ± 10.2 Male sex 46.1% Body mass idex, kg/m 2, mea ± SD a 28 ± 4.5 Ever smokers 39% Curret smokers 19% Pack-years (iqr) b 0 (0, 15.6) Systolic BP, mmhg ± 16.9 Diastolic BP, mmhg 84.0 ± 9.6 Atihypertesive therapy 37.5% Total cholesterol, mmol/l, mea ±SD a HDL cholesterol ± SD a 1.30 ± 0.32 Cholesterol-lowerig therapy 18.9% Triglycerides, mmol/l, mea ± SD a 1.70 ± 0.89 Diabetes mellitus preset 13% IMTcc, mm, mea ± SD a ± IMTmax, mm, media (iqr) b (0.07, 0.20) Vessel bifurcatios with plaques Noe 214 (27.9%) Oe 145 (18.9%) Two 174 (22.7%) Three 96 (12.5%) All four 138 (18.0%) TPT, cm, media (iqr) (0, 0.64) HDL, high-desity lipoprotei; IMT, itima media thickess; TPT, total plaque thickess; iqr, iterquartile rage. a Mea ad stadard deviatio (SD) is used for ormally distributed values. b Media ad iterquartile rage (iqr) is used for oormally distributed values.

4 230 M Griffi et al. Table 2 Associatio betwee ultrasoic measuremets ad cardiovascular disease (CVD) Ultrasoic measuremets Rage of measuremets Subjects studied CVD preset (%) Adjusted odds ratio a IMTcc (mm) Quartiles 1 st (5.4%) d (10.7%) 2.09 (0.98 to 4.46) 1.21 (0.52 to 2.77) 3 rd (19.1%) 4.10 (1.93 to 8.73) 1.27 (0.53 to 3.00) 4 th (25.4%) 5.92 (2.89 to 12.13) 1.27 (0.54 to 2.98) IMTmax (mm) Quartiles 1 st (3.5%) d (9.9%) 3.00 (1.25 to 7.19) 1.63 (0.64 to 4.14) 3 rd (14.5%) 4.65 (2.06 to 10.50) 1.85 (0.76 to 4.49) 4 th (32.3%) (6.06 to 28.13) 2.94 (1.22 to 7.07) Total plaque thickess (cm) Quartiles 1 st No plaques (2.3%) d (5.3%) 2.37 (0.78 to 0.20) 1.51 (0.48 to 4.76) 3 rd (13.4%) 6.59 (2.48 to 17.54) 2.93 (1.04 to 8.25) 4 th (39.2%) (10.81 to 70.05) 6.87 (2.42 to 19.43) a Adjusted for age, sex, pack-years, systolic blood pressure, total cholesterol, diabetes; also, admiistratio of cholesterol-lowerig therapy ad atihypertesive therapy. Odds ratios for the associatio of each ultrasoic measuremet (quartiles of IMTcc, IMTmax ad TPT) with cardiovascular disease are show i Table 2. IMTmax ad TPT have a stroger associatio with the presece of cliical cardiovascular disease tha IMTcc. After adjustig for age, sex, pack years, systolic blood pressure (SBP), total cholesterol, lipid-lowerig therapy, ad atihypertesive therapy oly the 4th quartile of IMTmax ad the 3rd ad 4th quartile of TPT were sigificat; IMT was o loger sigificat. Odds ratios for the associatio betwee the total umber of bifurcatios (carotid ad femoral) with plaque, umber of carotid bifurcatios ad umber of commo femoral bifurcatios with cardiovascular disease are show i Table 3. The presece of two carotid plaques or eve oe femoral plaque was associated with a icreased prevalece of CVD (29.1% ad 15.9%, respectively) (OR 2.21 ad 2.68, respectively). However, whe both carotid ad femoral vessels were combied the presece of plaques i three vessels was associated with a markedly icreased Table 3 Associatio betwee carotid bifurcatio plaques, femoral bifurcatio plaques, umber of bifurcatios with plaque ad cardiovascular disease (CVD) Carotid plaques Subjects studied CVD preset (%) femoral plaques femoral plaques ad risk factors a (4.8%) (11.2%) 2.49 (1.26 to 4.92) 1.86 (0.92 to 3.77) 1.37 (0.65 to 2.89) (29.1%) 8.08 (4.51 to 14.48) 4.35 (2.35 to 8.07) 2.21 (1.12 to 4.33) Femoral plaques Subjects studied CVD preset (%) carotid plaques carotid plaques ad risk factors a (4.1%) (15.9%) 4.46 (2.30 to 8.67) 3.75 (1.90 to 7.39) 2.68 (1.31 to 5.50) (32.9%) (6.52 to 20.53) 7.37 (4.05 to 13.39) 3.70 (1.87 to 7.32) Bifurcatios with plaques Subjects studied CVD preset (%) risk factors a (2.3%) (6.9%) 3.10 (1.04 to 9.26) 2.51 (0.70 to 8.86) (9.2%) 4.23 (1.52 to 11.80) 2.53 (0.79 to 8.11) (25.0%) (5.12 to 37.88) 6.48 (2.03 to 20.74) (42.0%) (12.02 to 80.36) 9.07 (2.84 to 28.94) a Adjusted for age, sex, pack-years, systolic blood pressure, total cholesterol, diabetes; also admiistratio of cholesterol-lowerig therapy ad atihypertesive therapy.

5 Arterial wall chages ad cardiovascular disease 231 Table 4 Associatio of total plaque thickess (TPT) greater tha 0.52 cm (value with highest sesitivity 75.2% ad specificity 75.2% i ROC curve) with prevalece of cardiovascular disease: TPT > 0.52 cm idetifies 247 (32%) of the populatio that cotais 85/113 (75%) of the evets TPTcm Nodisease Disease < (94.6%) 28 (5.4%) 520 > (65.6%) 85 (34.4%) 247 Total 654 (85.3%) 113 (14.7%) 767 OR 9.20 (95% CI 5.79 to 14.61) PPV 34.4%; NPV 94.6%; LR 3.03 TPT, total plaque thickess; OR, odds ratio; PPV, positive predictive value; NPV, egative predictive value; LR, likelihood ratio. prevalece of CVD (29%) (OR 6.48). The presece of plaque i four vessels was associated with a eve higher prevalece of CVD (42.0%) (OR 9.07). A cut-off poit of total plaque thickess greater tha 0.52 cm (maximum combied sesitivity (75.2%) ad specificity (75.2%) determied from the ROC curve) idetified 247 (32%) of the populatio that cotaied 85 (75%) of the 113 idividuals with cliical cardiovascular disease (Table 4). The positive predictive value was 34.4%, egative predictive value 94.6% ad the likelihood ratio of a positive test result Subgroup aalysis has produced similar results for me ad wome. I me, the prevalece of CVD was 7.1% i the presece of TPT < 0.52 cm ad 38.2% i the presece of TPT 0.52 cm (OR 8.11; 95% CI 4.27 to 15.42). I wome, the prevalece of CVD was 4.5% i the presece of TPT < 0.52 cm ad 25.7% i the presece of TPT 0.52 cm (OR 7.37; 95% CI 3.53 to 15.37). Discussio I the populatio-based study of 767 idividuals preseted i this paper, the presece of plaque at three or four bifurcatios (idicatig the presece of both carotid ad femoral atherosclerosis) ad TPT (the sum of the thickest plaque preset i each of the four vessel bifurcatios scaed) appear to have a stroger associatio with the prevalece of cardiovascular disease tha IMTcc or IMTmax measuremets (Table 2). It has already bee demostrated by aother study that the sum of the maximum plaque thickess i both carotid bifurcatios has a sigificat correlatio with the left mai coroary artery atheroma, as assessed by itravascular ultrasoud. 9 I our study, the presece of plaques i the commo femoral artery is aother factor associated with cardiovascular disease (Table 3). As far as we kow, this is the first time that associatios betwee cardiovascular disease prevalece ad differet ultrasoic measuremets that iclude IMTcc, IMTmax, presece of plaque at the commo femoral bifurcatio, umber of vessels with plaque, ad total plaque thickess have bee compared i a sigle populatio study. The value of IMT as a surrogate ed-poit i epidemiological studies o atherosclerosis ad coroary artery disease is well established. Icreased IMT is associated with the presece ad extet of coroary artery disease, 1 9,13 ad progressio of IMT is associated with future coroary evets. 17 However, there is cotroversy about whether IMT measuremet is a better predictor of future myocardial ifarctio or stroke tha covetioal risk factors such as age, sex, hypertesio, hyperlipidemia, diabetes ad smokig, which ca be easily obtaied. The Natioal Cholesterol Educatio Program (NCEP) (Adult Treatmet Pael III) third report has stated that carotid IMT could be used as a adjuct i coroary heart disease (CHD) risk assessmet, thereby improvig the idetificatio of idividuals at high risk tha that revealed by major risk factors aloe. 18 Others have idicated that a sigle measuremet of IMT is of the same importace as commoly used risk factors i the predictio of coroary heart disease ad cardiovascular disease ad does ot add substatially whe used as a screeig tool to discrimiate subjects with high or low risk of coroary heart disease ad cardiovascular disease. 16 As idicated i the itroductio, the methodology of ultrasoic measuremets varies from measuremets of IMT of the commo carotid (IMTcc), 2,4,7 the thickest part of several measuremets of the carotid bifurcatio that by its ature icludes plaque thickess, 3 the mea of six sites i the carotid bifurcatio, 1,8 measuremet of the umber of plaques irrespective of their size 6,7,9 to measuremet of plaque area We have already demostrated i a earlier study that the presece of plaque has a stroger associatio with the prevalece of CVD tha IMTcc. 5 This is ot surprisig because IMTcc ad plaque size are quatitative traits with differet biological determiats: cardiovascular risk factors 19,20 ad gee polymorphisms such as TNFRSF1A R92Q ad PPARG P12A. 21 The results preseted i this paper should be iterpreted with cautio because they are derived from a cross-sectioal study; the predictive ability of these measures will be tested prospectively i the log-term follow-up of our study. Also, may of the patiets, as idicated i Table 1, are o atihypertesive, cholesterol-lowerig therapy ad atidiabetic drugs that have a potet ifluece o both carotid atherosclerosis ad the occurrece of cardiovascular evets. Thus, the effect of the classical risk factors o the developmet of cliical CVD may be uderestimated as compared to the ultrasoic measuremets. However, whe we adjusted for

6 232 M Griffi et al. atihypertesive ad cholesterol-lowerig therapy we foud that IMTmax, the presece of commo carotid ad femoral plaques, the total umber of bifurcatios with plaque preset ad total plaque thickess were still strogly associated with the presece of cliical CVD (Tables 2 ad 3). The fidigs of this study suggest that the presece, umber ad size of plaques have a stroger associatio with cliical cardiovascular disease tha ay IMT measuremets ad warrat further ivestigatio i large prospective studies to determie whether they are associated with the future developmet of cliical evets. Substatiatio of these fidigs ad their potetial associatio with future cardiovascular evets may provide a meas of better progostic idetifiers of idividuals at high risk tha the curretly used covetioal risk factors. Coflict of iterest disclosures Noe. Ackowledgemets This work was supported i part by a grat (41/50ΠE-2002) from the Cyprus Research Promotio Foudatio, PO Box 23422, 1683 Nicosia, Cyprus ad a grat from the Miistry of Health, Govermet of Cyprus, 10 Markou Drakou, 1040 Nicosia, Cyprus. We are also grateful to Lucas Tsagarides Trust for providig the research premises i the village of Pedoulas. Refereces 1 Chambless LE, Heiss G, Folsom AR, et al. Associatio of coroary heart disease icidece with carotid arterial wall thickess ad major risk factors: the Atherosclerosis Risk i Commuities (ARIC) Study, Am J Epidemiol 1997; 146: Bots ML, Hoes AW, Koudstaal PJ, Hofma A, Grobbee DE. Commo carotid itima media thickess ad risk of stroke ad myocardial ifarctio: the Rotterdam Study. Circulatio 1997; 96: O Leary DH, Polak JF, Kromal RA, Maolio TA, Burke GL, Wolfso Jr SK. Carotid-artery itima ad media thickess as a risk factor for myocardial ifarctio ad stroke i older adults. Cardiovascular Health Study Collaborative Research Group. 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