Comparison Between Measures of Atherosclerosis and Risk of Stroke The Rotterdam Study

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1 Compariso Betwee Measures of Atherosclerosis ad Risk of Stroke The Rotterdam Study M. Hollader, MD, PhD; A.E. Hak, MD, PhD; P.J. Koudstaal, MD, PhD; M.L. Bots, MD, PhD; D.E. Grobbee, MD, PhD; A. Hofma, MD, PhD; J.C.M. Wittema, PhD; M.M.B. Breteler, MD, PhD Backgroud ad Purpose Several measures of atherosclerosis predict the risk of stroke. However, a compariso betwee various measures of atherosclerosis is lackig, ad limited iformatio exists o the added value of idividual measures of atherosclerosis to cardiovascular risk factors. We compared differet measures of atherosclerosis i relatio to stroke. Methods The study was based o the prospective cohort of the Rotterdam Study ad icluded 6913 participats who did ot suffer from previous stroke. At baselie, carotid itima-media thickess ad plaques, akle-arm idex, ad aortic calcificatios were assessed; 3996 participats (53%) had measures of all studied markers of atherosclerosis. After a mea follow-up of 6.1 years, 378 strokes occurred. Data were aalyzed with Cox proportioal-hazards regressio ad Akaike iformatio criteria scores. Results Carotid itima-media thickess ad aortic calcificatios were related most strogly to the risk of stroke (relative risk, 2.23 ad 1.89; 95% cofidece iterval, 1.48 to 3.36 ad 1.28 to 2.80 for highest versus lowest tertile, respectively). The relatios betwee itima-media thickess, aortic calcificatios, ad carotid plaques ad stroke remaied after adjustmet for cardiovascular risk factors. Itima-media thickess ad aortic calcificatios were related to the risk of stroke idepedetly of each other. The relatio betwee akle-arm idex ad stroke disappeared after adjustmet for cardiovascular risk factors. Coclusios Carotid itima-media thickess ad aortic calcificatios are stroger predictors of icidet stroke tha carotid plaque or akle-arm idexes. They have additioal value to each other ad to classic risk factors ad may reflect differet processes. (Stroke. 2003;34: ) Key Words: atherosclerosis epidemiology risk factors Several oivasive measures of atherosclerosis icludig carotid artery itima-media thickess (IMT), carotid plaques, akle-arm idex, ad aortic calcificatios are related to the risk of stroke i the populatio. 1 4 Most studies focused o idividual measures of atherosclerosis; few studies have compared measures of atherosclerosis. 5 It is still uclear whether all measures of atherosclerosis reflect the same process. Carotid IMT is cosidered a marker of geeralized atherosclerosis. Carotid plaques ca be markers of geeralized atherosclerosis ad sources of emboli. 6 Recetly, it was reported that akle-arm idex may reflect oly a ufavorable cardiovascular risk profile. 3 Calcificatios i the vessel wall are cosidered to reflect the extet of atherosclerosis elsewhere. 7 Therefore, measures reflectig the amout of calcificatio i the atherosclerotic plaque such as aortic atherosclerosis 8 may be strogly related to stroke. Data o the cotributio of each idividual measure of atherosclerosis to See Editorial Commet, page 2372 classic cardiovascular risk factors i relatio to stroke are limited. 9 We evaluated ad compared the stregth of the relatio betwee carotid plaques, carotid IMT, akle-arm idex, ad aortic calcificatios i relatio to stroke i a populatio of elderly subjects. Materials ad Methods Populatio The study is part of the Rotterdam Study, a populatio-based cohort study o chroic ad disablig diseases i the elderly. All ihabitats of Ommoord, a district of Rotterdam, 55 years of age were ivited. People livig i homes for the elderly were icluded. Participatio rate of those ivited for the study was 78%; i total, 7983 subjects participated. 10 The Medical Ethics Committee of Erasmus Uiversity Rotterdam approved the study. Writte iformed coset to retrieve iformatio from treatig physicias was obtaied from all participats. Baselie measuremets were obtaied from 1990 through Received Jauary 10, 2003; fial revisio received Jue 11, 2003; accepted Jue 18, From the Departmet of Epidemiology ad Biostatistics (M.H., A.E.H., A.H., J.C.M.W., M.M.B.B.) ad Departmet of Neurology (M.H., P.J.K.), Erasmus Medical Ceter, Rotterdam, ad Julius Ceter for Health Scieces ad Primary Care, Uiversity Medical Ceter Utrecht, Utrecht (M.L.B., D.E.G.), the Netherlads. Correspodece to Moique M.B. Breteler, MD, PhD, Departmet of Epidemiology ad Biostatistics, Erasmus Medical Ceter Rotterdam, PO Box 1738, 3000 DR Rotterdam, Netherlads. m.breteler@erasmusmc.l 2003 America Heart Associatio, Ic. Stroke is available at DOI: /01.STR E 2367

2 2368 Stroke October ad cosisted of a home iterview ad 2 visits to the research ceter for physical examiatio. A total of 7721 participats were free of previous stroke. At the baselie visit to the research ceter, we assessed several measures of atherosclerosis: carotid IMT, carotid plaques, akle-arm idex, ad aortic calcificatios. The study populatio cosisted of 6913 persos who had assessmet of at least 1 measure of atherosclerosis. Assessmet of Atherosclerosis at Baselie Carotid IMT ad Carotid Plaques Participats uderwet B-mode ultrasoography of both carotid arteries. We measured IMT of the commo carotid artery ad presece of plaques i both carotid arteries accordig to a stadardized protocol as published previously. 1,6,11 Akle-Arm Idex The systolic blood pressure of the posterior tibial artery was measured o both sides with a 8-MHz cotiuous-wave Doppler probe (Hutleigh 500 D, Hutleigh Techology) ad a radom-zero sphygmomaometer. Sittig blood pressure of the right arm was measured twice with a radom-zero sphygmomaometer. Mea blood pressure was used to calculate the akle-arm idex for each leg. I the aalyses, we used the lowest measuremet. Because of possible measuremet artifacts reflectig the presece of rigid or calcified walls, 36 participats with a akle-arm idex 1.5 were excluded. Aortic Calcificatio Aortic calcificatio was diagosed by radiographic detectio of calcified deposits i the abdomial aorta. 8 At baselie, lateral abdomial films (T12 through S1) were made from a fixed distace while the subject was seated. Aortic calcificatios were cosidered preset whe liear desities were see i a area parallel ad aterior to the lumbar spie (L1 through L4). Baselie values for the extet of calcificatio were scored ito 5 categories accordig to the legth of the ivolved area (1 plaque, 0.5 to 1.0 cm; several dissemiated plaques, 2.5, 2.5 to 4.9, 5.0 to 9.9, ad 10 cm). The umbers of participats with data available o carotid IMT, plaques, akle-arm idex, ad aortic calcificatios were 5479, 5440, 6196, ad 5631, respectively. Data o all measuremets of atherosclerosis were available for 3996 participats (53% of the 6913 participats without previous stroke). Logistical reasos such as limited availability of ultrasoographers maily accouted for the fact that ot all measuremets were available for all participats. Furthermore, x-rays were ot take at the very begiig of the study. Because i most istaces a lack of measures of atherosclerosis was ot related to participat characteristics, we do ot thik that restrictio to persos with all measuremets has caused a serious selectio bias. Participats with all measures available were o average 4.6 years youger (95% cofidece iterval [CI], 4.2 to 5.1), were more ofte male (41% versus 38%; P 0.05 adjusted for age), had 2.6 mm Hg higher (95% CI, 1.5 to 3.7) systolic blood pressure, ad had 0.09-mmol/L-higher (95% CI, 0.0 to 0.1) total cholesterol levels compared with participats with missig values for 1 measures of atherosclerosis (adjusted for age ad/or sex). We observed o differeces i diastolic blood pressure, diabetes, smokig, ad cholesterol. Assessmet of Stroke History of stroke or trasiet ischemic attack at baselie was assessed ad verified as described previously. 6 Oce subjects eter the Rotterdam Study, they are cotiuously moitored for major evets through automated likage of the study database with files from geeral practitioers ad the muicipality. For reported evets, additioal iformatio was obtaied from hospital records. A eurologist (P.J.K.) reviewed iformatio o all possible strokes ad classified the stroke as defiite, probable, or possible. A stroke was defiite if the diagosis was based o typical cliical symptoms ad euroimagig excluded other diagoses. A stroke was cosidered probable if typical cliical symptoms were preset but euroimagig was ot performed. For fatal strokes, other causes of death, especially cardiac, should have bee excluded. A stroke was classified as possible if cliical symptoms were less typical ad euroimagig was ot performed or if a cardiac cause of death could ot be excluded i case of reported stroke. Subclassificatio ito hemorrhagic or ischemic stroke was based o euroimagig, which was available for 61% of all patiets. Follow-up was available for all participats util Jauary 1, Cardiovascular Disease Status ad Risk Factors Iformatio o curret health status ad medical history at baselie was obtaied with a computerized questioaire. All reported myocardial ifarctios were verified by medical records. History of itermittet claudicatio ad agia pectoris was assessed through the Rose questioaire. Nofastig blood samples were take, ad serum total cholesterol ad high-desity lipoprotei (HDL) cholesterol were measured with a automated ezymatic procedure. Hypertesio was defied as systolic blood pressure of 140 mm Hg or diastolic blood pressure of 90 mm Hg. Diabetes mellitus was defied as use of oral blood glucose lowerig drugs or isuli or radom or postload serum glucose level 11.0 mmol/l, accordig to the World Health Orgaizatio criteria. Atrial fibrillatio was assessed by ECG. A history of cardiovascular disease was coded if participats had a history of trasiet ischemic attack, myocardial ifarctio, agia pectoris, itermittet claudicatio, atrial fibrillatio, coroary bypass surgery, ad/or coroary agioplasty. Data Aalysis We evaluated the relatioship betwee carotid IMT, carotid plaques, akle-arm idex, ad aortic calcificatios ad risk of first-ever stroke ad cerebral ifarctio usig Cox regressio aalysis. Data were aalyzed i several ways. First, to check for gross deviatios from TABLE 1. Baselie Characteristics of the Study Populatio Study Populatio ( 6913) Age, y 69.5 (9.2) Female sex, % 60.3 Diastolic blood pressure, mm Hg 73.6 (11.7) Systolic blood pressure, mm Hg (22.4) Total cholesterol, mmol/l 6.6 (1.2) Hypertesio, % 33.9 HDL cholesterol, mmol/l 1.3 (0.4) Diabetes, % 10.0 Smokig, % Curret 22.7 Former 41.6 History of cardiovascular disease, % 24.4 History of myocardial ifarctio, % 11.5 Mea commo carotid IMT, mm 0.80 (0.16) Carotid plaque score 1.4 Akle-arm idex 1.06 (0.23) Aortic calcificatios, % Noe cm cm cm cm cm 2.2 Values represet meas (SD).

3 Hollader et al Measures of Atherosclerosis ad Risk of Stroke 2369 TABLE 2. Relative Risk of Stroke i Relatio to Measures of Atherosclerosis Measure of Atherosclerosis Carotid IMT At Risk, liearity, we assessed the risks i participats i tertiles, takig the least severe atherosclerosis as the referece. A composite atherosclerosis score was obtaied by addig up the scores for the separate measures of atherosclerosis (rage, 0 to 8). We further aalyzed carotid IMT ad akle-arm idex per-sd icrease ad carotid plaques ad aortic calcificatios per uit icrease. Aalyses were adjusted for age ad sex ad for diabetes mellitus (yes, o), smokig (curret, former, ever), systolic ad diastolic blood pressures, ad total ad HDL cholesterol levels. Results are preseted as relative risks with correspodig 95% CIs. We used Akaike optimal iformatio criteria (AIC) to evaluate the progostic ability of the measures of atherosclerosis compared with a referece model. 12 This method allows us to take both follow-up time ad differeces i umbers of degrees of freedom ito accout. The height of the AIC score reflects the progostic value; a positive score idicates that addig the measure of atherosclerosis results i a improvemet i the referece model. Patiets, Relative Risk* Relative Risk Low Itermediate ( ) 1.64 ( ) High ( ) 2.42 ( ) Per-SD icrease ( ) 1.28 ( ) Carotid plaques Low Itermediate ( ) 1.18 ( ) High ( ) 1.47 ( ) Per-category icrease ( ) 1.15 ( ) Akle-arm idex High Itermediate ( ) 0.99 ( ) Low ( ) 1.28 ( ) Per-SD decrease ( ) 1.13 ( ) Aortic calcificatio Low Itermediate ( ) 1.21 ( ) High ( ) 1.63 ( ) Per-category icrease ( ) 1.21 ( ) Composite score Low Itermediate ( ) 1.52 ( ) High ( ) 2.71 ( ) Per-category icrease ( ) 1.26 ( ) Rages for tertiles were 0.72, , 0.84 mm for IMT; 0, 1 2, 3 6 for carotid plaques; 1.01, , 1.17 for akle-arm idex; 0, 1 2, 3 5 for aortic calcificatios; 0 2, 3 4, 5 8 for compoud score. *Adjusted for age ad sex. Adjusted for age, sex, diabetes mellitus, smokig, systolic ad diastolic blood pressures, cholesterol ad HDL cholesterol levels, ad history of cardiovascular disease. The AIC was calculated as the 2 statistic of the sigificat chage for the exteded model compared with a referece model mius 2 times the umber of degrees of freedom. For these aalyses, we restricted ourselves to participats with iformatio available o all measures of atherosclerosis. We etered carotid IMT ad akle-arm idex as cotiuous variables ad carotid plaques ad aortic calcificatios as categorical variables ito the model. First, we used a model icludig age ad sex as referece. The, the referece model was expaded with diabetes mellitus, smokig, diastolic ad systolic blood pressures, total ad HDL cholesterol, ad history of cardiovascular disease. We further used stepwise regressio aalysis to assess which measures of atherosclerosis were idepedetly related to the risk of stroke ad cerebral ifarctio. Age ad sex were forced ito the model. Fially, we tested for iteractio betwee atherosclerosis ad smokig, diabetes, hypertesio, ad previous myocardial ifarctio.

4 2370 Stroke October 2003 TABLE 3. Relative Risk of Cerebral Ifarctio i Relatio to Measures of Atherosclerosis Measure of Atherosclerosis Carotid IMT At Risk, Results Table 1 shows baselie characteristics of the study populatio. A total of 378 strokes occurred durig a mea follow-up time of 6.1 years ( perso-years). Of these, 198 (52%) were cerebral ifarctios ad 29 (8%) were itracerebral hemorrhages. The umber of hemorrhages was too small to aalyze them separately. Participats i the highest tertiles of carotid IMT, carotid plaques, ad aortic calcificatio ad the lowest tertile of the akle-arm idex had a sigificatly icreased risk compared with those i the referece tertiles (Table 2). We observed a 4-fold icreased risk of stroke for participats i the highest tertile of the composite atherosclerosis score. Additioal adjustmet for cardiovascular risk factors ad history of cardiovascular disease atteuated the risk estimates, but the risks Patiets, Relative Risk* Relative Risk Low Itermediate ( ) 2.26 ( ) High ( ) 2.30 ( ) Per-SD icrease ( ) 1.20 ( ) Carotid plaques Low Itermediate ( ) 1.38 ( ) High ( ) 1.55 ( ) Per-category icrease ( ) 1.09 ( ) Akle-arm idex High Itermediate ( ) 0.77 ( ) Low ( ) 1.02 ( ) Per-SD decrease ( ) 1.09 ( ) Aortic calcificatio Low Itermediate ( ) 1.73 ( ) High ( ) 2.10 ( ) Per-category icrease ( ) 1.21 ( ) Composite score Low Itermediate ( ) 1.72 ( ) High ( ) 2.63 ( ) Per-category icrease ( ) 1.22 ( ) Rages for tertiles were 0.72, , 0.84 mm for IMT; 0, 1 2, 3 6 for carotid plaques; 1.01, , 1.17 for akle-arm idex; 0, 1 2, 3 5 for aortic calcificatios; 0 2, 3 4, 5 8 for compoud score. *Adjusted for age ad sex. Adjusted for age, sex, diabetes mellitus, smokig, systolic ad diastolic blood pressures; cholesterol ad HDL cholesterol levels, ad history of cardiovascular disease. remaied sigificatly icreased, except for those related to a low akle-arm idex. Table 3 shows that the results were largely similar for cerebral ifarctios. Table 4 shows the additioal values for the differet measures of atherosclerosis beyod traditioal cardiovascular risk factors. It shows that IMT ad aortic calcificatios had the highest added value to predict stroke compared with a model icludig age ad sex (model 1). The additioal value of both measures remaied compared with a model with cardiovascular disease (model 2). The AIC scores dimiished whe the referece model was expaded with history of cardiovascular disease (model 3). Akle-arm idex performed worst of all ad lost the additioal value for stroke compared with a referece model icludig age, sex, ad cardiovascular risk factors (model 2).

5 Hollader et al Measures of Atherosclerosis ad Risk of Stroke 2371 TABLE 4. AIC for the Measure of Atherosclerosis ad Percetages of the Maximal AIC Score AIC vs Model 1 AIC vs Model 2 AIC vs Model 3 Percet of Maximal AIC Score Percet of Maximal AIC Score Percet of Maximal AIC Score Outcome Measure of Atherosclerosis AIC Score AIC Score AIC Score Stroke IMT * * * Carotid plaques * * Akle-arm idex * Aortic calcificatios * * * Cerebral ifarctio IMT * Carotid plaques * Akle-arm idex * Aortic calcificatios * Model 1 icludes age ad sex; model 2, age, sex, diabetes mellitus, smokig, systolic ad diastolic blood pressures, ad cholesterol ad HDL cholesterol levels; model 3, age, sex, diabetes mellitus, smokig, systolic ad diastolic blood pressures, cholesterol ad HDL cholesterol levels, ad history of cardiovascular disease. *P 0.01; P 0.05; P Subsequetly, we aalyzed all measures of atherosclerosis i a stepwise regressio model i which we forced the variables age ad sex. For both stroke ad cerebral ifarctio, carotid IMT ad aortic calcificatios were icluded (P 0.05). Fially, we failed to fid iteractios betwee carotid IMT ad aortic calcificatios ad diabetes, hypertesio, smokig, ad previous myocardial ifarctio (P 0.05). The results were similar for stroke ad cerebral ifarctio. Discussio I our populatio-based study of 6943 participats, we foud that carotid IMT ad aortic calcificatios were the strogest predictors of stroke. Carotid plaques ad akle-arm idex were less strog predictors. The relatio betwee akle-arm idex ad stroke was o loger statistically sigificat whe cardiovascular risk factors were take ito accout. Carotid IMT ad aortic calcificatios predict the risk of stroke idepedetly of each other. This idicates that they may represet differet pathophysiological mechaisms. Before we iterpret our results, some methodological issues eed to be addressed. First, some aalyses were restricted to participats with assessmet of all measures of atherosclerosis. Because atherosclerosis measures were missig mostly for reasos that were idepedet of participat characteristics ad the overall vascular risk profile was ot very differet betwee people with ad without complete data o all measures of atherosclerosis, we thik that this has ot caused a selectio bias. Furthermore, misclassificatio of atherosclerosis could have occurred, ad we may have misclassified some strokes or subtypes of stroke. We restricted our aalysis to CTor MRI-cofirmed cerebral ifarctios to reduce misclassificatio. However, classificatio of atherosclerosis was doe by researchers blided to stroke status ad vice versa. Hece, if misclassificatio had occurred, it is likely to be odifferetial, leadig to uderestimatio of the observed effects. The mai issue i our study was to determie which measures of atherosclerosis are strogest predictors of the risk of stroke ad cerebral ifarctio. Carotid IMT ad akle-arm idex were cotiuous measures; carotid plaques ad aortic calcificatios were categorical measures. Evaluatio of relative risks i categories allowed us to compare the relative risks. IMT has bee ivestigated widely as a measure of geeralized atherosclerosis. Our results show the robustess of the relatio betwee IMT ad stroke. Presece of aortic calcificatios was a importat risk idicator for stroke, eve whe iformatio o carotid IMT or cardiovascular risk factors was take ito accout. Two mechaisms could explai the persistece of such associatio. First, calcificatios could reflect arterial stiffess, leadig to hypertesio ad stroke. The relatioships remaied sigificat after adjustmet for blood pressure, ad arterial stiffess has ot cosistetly bee show to be a risk factor for stroke. 13 Still, this hypothesis should ot be overlooked because 1 measuremet of blood pressure is a poor reflectio of the lifetime exposure. Aother explaatio to cosider is that calcificatios may represet the presece of atherosclerotic lesios i the aortic arch or carotid arteries from which emboli ca be released. A plausible explaatio for our fidig that IMT ad aortic calcificatios are related to stroke idepedetly of each other is that both markers of atherosclerosis reflect differet processes, as we described. Akle-arm idex was the poorest predictor for stroke because it lost its predictive ability after cardiovascular risk factors were take ito accout. This result supports the fidigs by the other populatio-based cohort studies i which the relatio betwee akle-arm idex ad stroke also dimiished after adjustmet for cardiovascular risk factors. 14 Our study cofirms that akle-arm idex has little progostic ability beyod traditioal risk factors for stroke ad cerebral ifarctio. I summary, carotid IMT ad aortic calcificatios are the strogest predictors of stroke. Carotid IMT, plaques, ad aortic calcificatios have additioal value to traditioal cardiovascular risk factors. The results of our study merit further research o idividual stroke risk assessmet that icludes measures of atherosclerosis. I additio to carotid IMT, iformatio o calcificatios i the vessel wall may help i idetifyig people at high risk of stroke. Ackowledgmets The Netherlads Orgaizatio for Scietific Research (NWO), Health ad Developmet Research Coucil (ZON), ad Muicipality

6 2372 Stroke October 2003 of Rotterdam supported the Rotterdam Study. Dr Hollader is supported by grat from NWO. Dr Bots is supported i part by grat of the Netherlads Heart Foudatio. Dr Breteler is a fellow of the Royal Netherlads Academy of Arts ad Scieces. We are grateful to the participats, geeral practitioers, ad field workers i the Rotterdam Study. We thak Ige Haumerse ad Toos Stehma for their skillful cotributio to the carotid ultrasoud ad aortic calcificatio measuremets. Refereces 1. 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: Polak JF, Shemaski L, O Leary DH, Lefkowitz D, Price TR, Savage PJ, Brat WE, Reid C. Hypoechoic plaque at US of the carotid artery: a idepedet risk factor for icidet stroke i adults aged 65 years or older: Cardiovascular Health Study. Radiology. 1998;208: Tsai AW, Folsom AR, Rosamod WD, Joes DW. Akle-brachial idex ad 7-year ischemic stroke icidece: the ARIC study. Stroke. 2001;32: Iribarre C, Sidey S, Sterfeld B, Brower WS. Calcificatio of the aortic arch: risk factors ad associatio with coroary heart disease, stroke, ad peripheral vascular disease. JAMA. 2000;283: O Rourke RA, Brudage BH, Froelicher VF, Greelad P, Grudy SM, Hachamovitch R, Pohost GM, Shaw LJ, Weitraub WS, Witers WL Jr. America College of Cardiology/America Heart Associatio expert cosesus documet o electro-beam computed tomography for the diagosis ad progosis of coroary artery disease. J Am Coll Cardiol. 2000;36: Hollader M, Bots ML, Del Sol AI, Koudstaal PJ, Wittema JC, Grobbee DE, Hofma A, Breteler MM. Carotid plaques icrease the risk of stroke ad subtypes of cerebral ifarctio i asymptomatic elderly: the Rotterdam Study. Circulatio. 2002;105: Vliegethart R, Hollader M, Breteler MM, va Der Kuip DA, Hofma A, Oudkerk M, Wittema JC. Stroke is associated with coroary calcificatio as detected by electro-beam CT: the Rotterdam Coroary Calcificatio Study. Stroke. 2002;33: Wittema JC, Grobbee DE, Valkeburg HA, va Hemert AM, Stije T, Burger H, Hofma A. J-shaped relatio betwee chage i diastolic blood pressure ad progressio of aortic atherosclerosis. Lacet. 1994;343: del Sol AI, Moos KG, Hollader M, Hofma A, Koudstaal PJ, Grobbee DE, Breteler MM, Wittema JC, Bots ML. Is carotid itima-media thickess useful i cardiovascular disease risk assessmet? The Rotterdam Study. Stroke. 2001;32: Hofma A, Grobbee DE, de Jog PT, va de Ouwelad FA. Determiats of disease ad disability i the elderly: the Rotterdam Elderly Study. Eur J Epidemiol. 1991;7: Bots ML, Hofma A, De Jog PT, Grobbee DE. Commo carotid itima-media thickess as a idicator of atherosclerosis at other sites of the carotid artery: the Rotterdam Study. A Epidemiol. 1996;6: Harrell FE Jr, Lee KL, Mark DB. Multivariable progostic models: issues i developig models, evaluatig assumptios ad adequacy, ad measurig ad reducig errors. Stat Med. 1996;15: Lehma ED, Hopkis KD, Joes RL, Rudd AG, Goslig RG. Aortic distesibility i patiets with cerebrovascular disease. Cli Sci (Colch). 1995; 89: Newma AB, Siscovick DS, Maolio TA, Polak J, Fried LP, Borhai NO, Wolfso SK. Akle-arm idex as a marker of atherosclerosis i the Cardiovascular Health Study: Cardiovascular Heart Study (CHS) Collaborative Research Group. Circulatio. 1993;88: Editorial Commet Vascular Thickess ad Calcificatio as Markers of Atherosclerotic Burde The study by Hollader et al 1 provides a ucommo opportuity to directly compare the predictive value of various oivasive tests of atherosclerotic burde for stroke i commuity dwellers. The study icluded a cohort of 7000 stroke-free subjects. Slightly more tha half of the subjects had a complete set of measures of carotid plaque, carotid itima-media thickess (IMT), akle-arm idex, ad aortic calcificatio. Study participats were followed up for a mea of 6.1 years. O the basis of poit estimates, measures of carotid IMT ad aortic calcificatios were stroger determiats of stroke tha measures of carotid plaque ad akle-arm idex. Carotid IMT, the most potet risk factor assessed i the study, imparted a relative risk of stroke of 2.23 for values i the highest tertile. Akle-arm idex, the least potet risk factor, imparted a relative risk of stroke of 1.55 for values i the lowest tertile. Ivestigators also foud that carotid IMT ad aortic calcificatios were idepedet risk factors. Statistical idepedece suggests that differet pathophysiological processes may cause IMT ad vascular calcificatios ad that these markers are ot simply measures of atherosclerotic burde iduced by so-called classic risk factors. B-mode ultrasoographic measuremet of IMT of the extracraial carotid arteries assesses at least 2 resposes of the blood vessel wall to cardiovascular risk factors. Itimal thickeig resultig from cellular accumulatio ad matrix depositio ca be see i ormal agig of the vascular system, eve i the absece of atherosclerotic plaque. 2 Medial thickeig caused by smooth muscle cell hypertrophy is closely related to arterial hypertesio, 3 but the precise stimulus is ot kow. 4 Vascular calcificatio i the form of hydroxyapatite begis early i the atherosclerotic process with microscopic amouts at the preatheroma stage (type III plaque) accordig to the histological classificatio system of Stary et al. 5,6 Such calcium deposits commoly occur i the basal aspect of the itima. Boe morphogeetic proteis ad ocollageous matrix proteis associated with boe mieralizatio are preset i atherosclerotic plaques. 7,8 Extracellular matrix vesicles ad ijured smooth muscle cell orgaelles may become idi for calcium precipitatio. 9,10 Moreover, plaque mieralizatio is related to extracellular calcium ad phosphate cocetratios 11 ad may be directly or idirectly iduced by oxidized or otherwise modified lipids. 12,13 There is substatial iteridividual variability i the extet of atherosclerosis at every level of exposure to risk factors. 14 Recet studies suggest a geetic basis for developig IMT ad

7 Hollader et al Measures of Atherosclerosis ad Risk of Stroke 2373 vascular calcificatio. To determie the extet of the familial aggregatio of carotid IMT i the presece of type 2 diabetes, Lage et al 15 studied 252 idividuals with type 2 diabetes from 122 families. The age-, sex-, ad race-adjusted heritability estimate for carotid IMT was 32%. After further adjustmet for total cholesterol, hypertesio, ad curret smokig status, the heritability estimate rose to 41%. Peyser et al 16 quatified the relative cotributios of measured risk factors ad geetic iflueces o coroary artery calcificatio (CAC) measured by electro beam CT i 698 asymptomatic adults from 302 families. Before adjustmet for ay risk factors, 43.5% of the variatio i CAC quatity was attributable to geetic factors. After adjustmet for CAC risk factors (age, sex, fastig glucose level, systolic blood pressure, pack-years of smokig, ad low-desity lipoprotei cholesterol), 41.8% of the residual variatio i CAC quatity was attributable to geetic factors. Clearly, the search for geetic factors that ifluece the susceptibility to cardiovascular risk factors must cotiue. Carotid IMT ad vascular calcificatios are modifiable. Cotrolled studies show that cholesterol-lowerig medicatios ca favorably chage both carotid IMT ad vascular calcificatios. I the Cholesterol Lowerig Atherosclerosis Study (CLAS), takig colestipol ad iaci caused sigificat progressive reductio i carotid IMT at 2 ad 4 years, whereas placebo-treated patiets showed sigificat icreases over the same period. 17 The Asymptomatic Carotid Artery Progressio Study (ACAPS) showed that, for patiets ot takig warfari, the mea maximum carotid IMT progressio curves ra parallel for lovastati (20 to 40 mg/d) ad placebo groups for 6 to 12 moths. 18 Thereafter, the curves sigificatly diverge, ad the lovastati group showed IMT regressio (aualized progressio rates, versus mm/year). The Moitored Atherosclerosis Regressio Study (MARS) of 188 patiets with agiographically defied coroary atherosclerosis cofirmed that lovastati (80 mg/d) ca favorably affect carotid IMT. 19 The effects of cholesterol-lowerig drugs o vascular calcificatio has bee less studied. However, a prospective study of patiets with low-desity lipoprotei cholesterol levels 130 mg/dl showed that the media aualized absolute icrease i coroary calcificatio volume measured by electro beam tomography sigificatly fell from 25 mm 3 while utreated to 11 mm 3 whe treated with cerivastati. 20 Whether testig for IMT ad vascular calcificatio will become compoets of routie cliical care depeds o whether the results of such testig will have direct therapeutic cosequeces. At preset, there are o pharmacotherapies specifically for vascular wall thickeig or calcificatio beyod what is curretly beig prescribed for treatig classic risk factors like hyperlipidemia ad hypertesio. James F. Meschia, MD, Guest Editor Departmet of Neurology Thomas C. Gerber, MD, PhD, Guest Editor Divisio of Iteral Medicie ad Cardiovascular Diseases ad Departmet of Radiology Mayo Cliic Jacksoville, Florida Refereces 1. Hollader M, Hak AE, Koudstaal PJ, Bots ML, Grobbee DE, Hofma A, Wittema JCM, Breteler MMB. 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