Noninvasive Defin~tion of Anatomic Coronary Artery Disease by Ultrafast Computed Tomographic Scanning: A Quantitative Pathologic Comparison Study

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1 1118 Nvember : Nninvasive Defin~tin f Anatmic Crnary Artery Disease by Ultrafast Cmputed Tmgraphic Scanning: A Quantitative Pathlgic Cmparisn Study D. BRENT SIMONS, MD, ROBERT S. SCHWARTZ, MD, FACC, WILLIAM D. EDWARDS, MD,t FACC, PATRICK F. SHEEDY, MD,:j: JEROME F. BREEN, MD,:j: JOHN A. RUMBERGER, MD, FACC, PHD Rchester, Minnesta Objectives. The aim f this study was t determine the relatin between crnary artery calcificatin detected by ultrafast cm puted tmgraphic scanning and histpathlgic crnary artery disease. Backgrund. Recent studies suggest that discrete crnary artery calcificatin as visualized by ultrafast cmputed tmgraphic scanning may facilitate the nninvash'e detectin r estimatin, r bth, f the in situ extent f crnary disease. Such quantitative relatins have nt been established. Methds. Thirteen cnsecutive perfusin-fixed autpsy hearts (frm eight male and five female patients aged 17 t 83 years) were scanned by ultrafast cmputed tmgraphic scanning in cntiguus 3-mm tmgraphic sectins. The majr epicardial arteries were dissected free, psitined lngitudinally and scanned again in crss sectin. Crnary artery calcificatin in a crnary segment was defined as the presence f ne r mre vxels with a cmputed tmgraphic density > 130 Hunsfield units. Each epicardial artery was sectined lngitudinally, stained and measured with a planimeter fr quantificatin f crss-sectinal and athersclertic plaque areas at 3-mm intervals, crrespnding t the cmputed tmgraphic scans. A ttal f 522 paired crnary cmputed tmgraphic and histlgic sectins were studied. Results. Direct relatins were fund between ultrafast cmputed tmgraphic scanning crnary artery calcium burden and athersclertic plaque area and percent lumen area stensis. Hwever, the range fr plaque area r percent lumen stensis, r bth, assciated with a gihn calcium burden was brad. Three hundred thirty-ne crnary segments shwed n calcificatin by cmputed tmgraphy. Althugh athersclertic disease was fund in several crrespnding pathlgic specimens, >97% f these nncalcified segments were assciated with nnbstructive disease «75% area stensis); if n calcificatin was determined in an entire crnary vessel, all crrespnding crnary disease was fund t be nnbstructive. T determine the relatin between arterial calcificatin and any athermatus disease, cmputed tmgraphic calcium burden fr each segment was paired with the histlgic absence r presence f disease. Ultrafast cmputed tmgraphic scanning had a sensitivity and specificity f 59 % and 90% and a negative and psitive predictive value f 65% and 87%, respectively. A direct crrelatin was fund (r = 0.99) between ttal calcium burden calculated frm tmgraphic scans f the heart as a whle and scans f the arteries btained in crss sectin. Cnclusins. The detectin f crnary calcificatin by ultrafast cmputed tmgraphic scanning is highly predictive f the presence f histpathlgic crnary disease, but the use f this technique t define the extent f crnary disease may be limited. Hwever, the absence f crnary calcificatin at any site is highly specific fr the absence f bstructive disease. (J Am Cli CardiI1992;20:1l18-26) Crnary artery disease is a leading cause f mrtality and mrbidity in industrialized natins. Current methds t screen fr its absence r presence, such as rutine treadmill exercise testing r radinuclide exercise testing, r bth, Frm the Departments f Cardivascular Diseases and Internal Medicine. tlabratry Medicine and Pathlgy and Wiagnstic Radilgy. May Clinic and Fundatin, Rchester, Minnesta. This study was supprted by an Established Investigatr Award frm the American Heart Assciatin, Dallas. Texas t Dr. Rumberger, Natinal Heart, Lung, and Bld Institute Grant Bethesda. Maryland and the May Fundatin. Rchester. Manuscript received January 17, 1992: revised manuscript received April accepted April 22, Address fr crrespndence: Jhn A. Rumberger, MD. PhD. Department f Cardivascular Diseases and Internal Medicine, May Clinic, 200 First Street, Suthwest. Rchester. Minnesta by the American Cllege f Cardilgy detect lesins that are flw limiting and thus lead t cardiac ischemia during stress. Hwever, acute mycardial infarctin r sudden death, r bth, is ften the first clinical presentatin f crnary artery disease (1). Evaluatin f flw-limiting lesins may als nt be useful in predicting thse patients wh later have a mycardial infarctin. The seminal study by Little et al. (2) shwed that nly 34% f patients wh had a mycardial infarctin after underging baseline crnary angigraphy had the infarctin at a site assciated with the artery that previusly demnstrated the mst severe stensis. Thus, a methd is needed that will detect athersclertic plaque befre it is large enugh t limit flw. Crnary artery calcificatin is bth a sensitive and a /92/$5.00

2 Nvember : SIMONS ET AL specific marker fr the presence f crnary artery athersclersis (3-5). Flurscpy and cnventinal cmputed tmgraphic scanning (6,7) can detect calcificatin, but Agatstn et al. (8) recently demnstrated that ultrafast cmputed tmgraphy is mre sensitive and specific than flurscpy fr quantifying the presence f crnary artery calcificatin. Ultrafast cmputed tmgraphy has advantages ver cnventinal cmputed tmgraphy because f its rapid scan acquisitin times (50 r 100 ms/image), which, facilitated by excellent spatial reslutin (:51 mm), are applicable t quantificatin f in viv cardiac anatmy and functin. Thus, this methd has been suggested as a cnvenient methd f screening fr crnary artery disease, particularly in asymptmatic, high risk subgrups f the general ppulatin. The examinatin t identify crnary artery calcificatin is nninvasive and easily perfrmed and des nt require use f intravenus cntrast medium. Hwever, a direct relatin between crnary artery calcificatin detected by ultrafast cmputed tmgraphic scanning and the extent f histpathlgic athermatus disease at the same anatmic site has nt been previusly established. The purpse f the current investigatin was threefld: t determine in situ the nature f the relatin between crnary artery calcificatin detected by ultrafast cmputed tmgraphic scanning and the quantitative extent f crnary artery disease; t determine the relatin between the extent f crnary artery disease and the absence f calcificatin identified by this technique, and t define the sensitivity and specificity f this technique fr detecting any athersclertic plaque in segments f human crnary arteries. Methds UJtrafast cmputed tmgraphic scanner. The ultrafast cmputed tmgraphic scanner (Imatrn C-l(0) is a unique electrn beam device with n mving parts (ther than the scanning gantry) that has previusly been shwn (9-13) t prvide quantitative assessment f cardiac size, shape and functin. This device can be perated in tw mdes: 1) a high tempral reslutin mde allwing electrcardigraphic (ECG) triggering f images frm multiple cardiac planes at a rate f 17 frames/s, fr use in standard cardiac functinal assessment, and 2) a high spatial reslutin, l00-ms singlelevel mde used fr radilgic applicatins (that is, rutine chest and abdminal cmputed tmgraphy). In the latter mde, the device is capable f perfrming ECG-triggered r manually triggered 3-, 6- r t-mm thick cntiguus tmgrams per level at a clinical rate f up t 40 images in 70 s. Fr the present study, loo-ms, 3-mm thick tmgrams were acquired by manual trigger with use f a 22-cm field f view and a matrix size f 512 x 512. The individual vxel size was nminally 0.58 x 0.58 x 3.0 mm. Crnary artery specimens. Thirteen cnsecutive autpsy hearts were btained frm 13 patients, 8 men and 5 wmen ranging in age frm 17 t 83 years (mean 43.5). The causes f death varied; nly tw patients had an antemrtem diagnsis f crnary athersclersis, and bth died after a mycardial infarctin. Of the remaining II patients, 6 died f trauma, 3 f metastatic carcinma, 1 f suicide and 1 f a gun sht wund. Each heart was pressure perfusin fixed with frmalin at 70 mm Hg t maintain crnary anatmic integrity. The hearts were scanned by ultrafast cmputed tmgraphy during tw separate sessins. In the first scan the heart was imaged as a whle t mimic acquisitin that culd be accmplished in the clinical situatin. Fr this prtin f the study, each heart was imaged in the standard transaxial psitin; each was scanned serially frm base t apex in 3-mm cntiguus tmgraphic sectins with use f the high reslutin mde and l00-ms scan time. Fr the secnd imaging sequence, the three majr epicardial crnary arteries were carefully dissected and separated frm the underlying mycardium, straightened and pinned t a backbard. A secnd set f 3-mm cntiguus scans was acquired perpendicular t the lngitudinal directin at each crss sectin. The mst prximate image was btained at the anatmic rigin f each crnary artery. The left main crnary artery was included as part f the left anterir descending crnary vessel. After the secnd scan, crss-sectinal histlgic sectins were prepared every 3 mm fr each crnary artery t crrespnd t each 3-mm cmputed tmgraphic image. Representative 5-JLm thick hematxylin-esin, and elastic van Giesn stains were made at each 3-mm sectin. Histlgic sectining cntinued up t apprximately 9 em fr each artery r until the arterial diameter was t small t sample prperly. Frm this ttal f 39 crnary arteries (13. x 3 epicardial vesselslheart), 522 histlgic sectins were prepared. Each histlgic sectin was examined bth qualitatively and quantitatively. One f us (W.n.E.), an experienced cardiac pathlgist, carefully reviewed each histlgic specimen and assigned t each a qualitative numeric scre f (n athersclertic disease), 1 (25% area bstructin), 2 (25% t 50% stensis), 3 (50% t 75% stensis) r 4 (>75% stensis). Each crnary segment that demnstrated qualitatively the presence f crnary disease was als quantified by light micrscpy fr the extent f athersclersis by determining the crss-sectinal, lumen and athersclertic plaque areas with quantitative planimetry. Fr each histlgic sectin, a percent lumen area stensis f 0% (n histlgic disease) and 100% (ttal bstructin by athersclertic disease) was calculated. The histlgic sectins were analyzed in randm fashin with the reviewers unaware f the results f the cmputed tmgraphic examinatins. Each ultrafast cmputed tmgraphic scanning image fr bth image sets was analyzed with use f cnventinal imaging sftware supplied by the manufacturer. Frm each scan, the examiner is able t identify and visually inscribe a regin f interest that cntains the tmgraphic crnary sectin. The image-prcessing sftware then autmatically

3 1120 SIMONS ET AL. CLTRAFAST COMPUTED TOMOGRAPHY IN CORONARY DISEASE Nvember I, 1992: Figure 1. A, Ultrafast cmputed tmgraphic (CT) scan acquired at the base f an intact human heart that was perfusin fixed at the time f pstmrtem examinatin. This image was acquired in the IOO-ms single-slice mde with a tmgraphic thickness f 3 mm. This scan images prximal prtins f the left anterir descending and circumflex crnary arteries. The prminent high cmputed tmgraphic densities in the regin f the left anterir descending artery are absent frm the adjacent circumflex vessel. The peak cmputed tmgraphic densities in the circumscribed regins f interest and the number f vxels with a cmputed tmgraphic density > 130 Hunsfield units (HU) (representing areas f discrete crnary artery calcificatin) are indicated in the margins. B, Ultrafast cmputed tmgraphic scan frm the same heart but at the mid-heart level, nw shwing a prximal sectin f the right crnary artery in the anterir atriventricular grve. LA = left atrial cavity; RA = right atrial cavity; RV = right ventricular cavity. searches the inscribed regin f interest and determines the cmputed tmgraphic density f the individual vxels within the regin. The presence f crnary artery calcificatin was defined as any vxel within the regin f interest with a cmputed tmgraphic density > 130 Hunsfield units in a fashin similar t that emplyed by Agatstn et al. The scan data f each intact heart usually cnsisted f 40 3-mm thick cntiguus images. Fr each 3-mm thick tmgram, the right, left anterir descending (including the left main) and left circumflex crnary arteries were identified (Fig. Fr each individual crnary segment in each tmgraphic sectin, the number f vxels with a cmputed tmgraphic density> 130 H was determined and termed the "calcium burden" fr that crnary segment. When the analysis was cmpleted, the ttal calcium burden fr crnary artery segments individually, r summed fr a vessel r the heart as a whle, culd be calculated directiy. The scan data fr each dissected crnary artery usually cnsisted f 30 3-mm thick images/artery. With use f the same prcedures as described, each 3-mm thick cmputed tmgraphic image was analyzed, and fr each crnary artery segment, the number f vxels > 130 H in each 3-mm slice quantified (Fig. 2). T cmplete the analysis, the dissected crnary artery ultrafast cmputed tmgraphic scanning data and the crrespnding representative histlgic data fr each crnary artery were paired and entered int a data base. Because care was taken t match each 3-mm slice in the dissected artery scans with the representative histlgic sectin fr the crrespnding 3-mm slice, a direct cmparisn fr each vascular segment culd then be perfrmed. Fr each segment, data n the calcium burden (btained frm cmputed tmgraphic scan analysis) and the crrespnding athersclertic plaque area, crss-sectinal lumen narrw-

4 JACC V!' 20, N.5 Nvember 1,1992: SIMONS ET AL Figure 2. Same patient as in Figure 1. Ultrafast cmputed tmgraphic (CT) scans thrugh three crss sectins f the majr epicardial crnary arteries. Discrete high density calcificatin is present in the left anterir descending and right crnary arteries but absent this level) in the left circumflex vessel. Sftware analysis required the peratr t define the crnary artery regin f interest as shwn. The number f vxels with a density > 130 Hunsfield units (HU) and the peak cmputed tmgraphic density within that regin were then displayed and recrded fr each sample. These crss sectins d nt necessarily crrespnd t the tmgraphic sectins in Figure 1. ing and histlgic stensis grade (btained frm histlgic data) culd be cmpared directly. Statistics. Results are presented fr crnary artery calcium cntent (r calcium "burden") as discrete values (fr the number f vxels with a cmputed tmgraphic density ::::130 H). Athersclertic plaque area and lumen crsssectinal stenses are presented as discrete values r as minimal, maximal and mean fr each histlgic segment. Linear and plynmial (nnlinear) regressin mdeling was perfrmed with standardized methds. The level f significance was determined as p < 0.05 with use f a tw-tailed t test and standardized lk-up tables fr the analysis f cntinuus variables. Sensitivity, specificity and predictive accuracy were calculated by using standard 2 x 2 cntingency methds. Statistical significance fr analyses f discrete variables was perfrmed by using a chi-square analysis with significance set at p < Results Crnary artery calcificatin f intact heart versus dissected crnary artery specimens. Althugh the majr intent f the current study was t investigate the relatin between in situ crnary artery calcificatin and the extent f athersclertic disease, it is als imprtant t determine whether "ideal" scanning f the dissected specimens in a fashin perpendicular t the vessel's lng axis is apprximated by scanning f the heart as a whle. T make this cmparisn, the ttal sum f crnary artery calcificatins fund in each f the three epicardial crnary arteries was determined fr each f the 13 hearts by analysis f bth image sets. Fr each heart, the tw data pints were pltted and the results crrelated. There was a direct and highly significant crrelatin between the calcificatin detected in the crnary tree fr the hearts scanned as a whle (Fig. 3, r = 0.99, y = O.98x, p < 0.001). Thus ultrafast cmputed tmgraphic crnary artery scans f the heart as a whle t define crnary calcium burden yields, at least under the ptimal scanning cnditins f the current study, results nearly identical t crnary calcium burden determined frm tmgraphic imaging perpendicular t the vessel crss sectins. In situ crnary artery calcificatin and quantifiable extent f athersclertic disease. The paired data f calcium burden by ultrafast cmputed tmgraphic scanning and the quantitative histlgic extent f crnary athermatus disease were examined in tw ways, first as cntinuus variables and then as discrete variables. Fr each histlgic crnary artery sectin, the athersclertic plaque area was quantified Figure 3. Linear sum f the number f vxels within a given heart that displayed crnary artery ultrafast cmputed tmgraphic (CT) sectins with densities > 130 Hunsfield units (that is, ttal "calcium burden" per heart) fr all 13 pstmrtem hearts examined. Data cmpare calculatins made with the heart intact and imaged in a cnventinal fashin (abscissa) and calculatins made frm "ideal" crss-sectinal imaging f the crnary artery sectins individually (rdinate). The crrelatins are excellent. "Ideal" Scanning f Vessel Crss Sectin n - 13 y -.98 x, -.99 p <.001 OJll< ~ Scanning f the Heart as a Whle Sum 01 Vxa!s wilh CT Dens!ly >130 HU fr each Heart 750

5 1122 SIMONS ET AL. JACC Vl. 20, N.5 Nvember I, 1992: A. B. 20 plaque AREA (~,. mm) IS r' 0.71 II'" SEE'I.ae p' CAOUM BURDEN (, PIXELS' 130 HU) PLAQUE AREA (aquare mm) r 0.17,,'118 an ul P'.001 PERCENT LUMEN AREA STENOSIS 100~ ~ IJ ~~ 75~ IJ ~ 0 IJ S 0 ~ 8 ;; 0 i ~ c 13 II 0 8!l 13 B :::; 8 ~ 50a ~ ~ - 0 B c ~ ~..J :) 0 I=: ~ g ~ 0 C G ;; IJ [; s c 0= El IJ 000 IJ IJ B y 8.9 x i n 522 r 0.66 SEE - 24 p ( NUMBER OF VOXELS WITH DENSITY '130 Figure 5. Crnary artery calcium burden (number f crnary artery vxels n ultrafast cmputed tmgraphic scanning with a density > 130 Hunsfield units (HU) fr all specimens (n = 522) versus percent lumen area stensis determined in paired histlgic samples. There is a direct crrelatin between calcium burden and lumen area stensis, but the spread f the data limits the applicatin n a sample by sample basis. IJ 25 c ~ CT CALCIUM BURDEN (, PIXELS' 130 HU) PLAQUE AREA (aquare mm) P'.001 SEE' 1M ~~~~~~~~~~~~~~ 4 8 ~ IS 20 CT CAlOUM BURDEN (, PIXELS' 130 HU) Figure 4. Calcium burden as defined by ultrafast cmputed tmgraphic (CT) scanning (see text fr details) versus athersclertic plaque area per histlgic specimen fr the left anterir descending (A), right (B) and left circumflex (C) crnary arteries. Data are presented as mean values. Individual errr bars represent the maximal and minimal plaque areas determined frm analysis f all specimens within the epicardial arteries displaying a given value fr the calcium burden. The linear crrelatin in each panel represents analysis f the data frm all segments f a given crnary artery. There is a direct and linear crrelatin between increasing calcium burden as defined by cmputed tmgraphy and quantificatin f individual plaque area/segment. See text fr discussin. = mean lumen stensis; * = maximal lumen stensis; + = minimal lumen stensis. and cmpared with the crrespnding calcium burden fund in that sectin frm the dissected crnary artery cmputed tmgraphic scan data. Each f the majr epicardial crnary arteries-the left anterir descending, right and circumflex crnary arteries-was analyzed separately (Fig. 4, A t C). Overall, there was a direct linear relatin between athersclertic plaque area in any crnary artery sectin and the cmputed tmgraphic calcium burden fr that vascular segment (0.57 ::; r::; 0.76, p::; 0.001). Hwever, at any particular value fr calcium burden, the assciated athersclertic plaque area varied cnsiderably as seen by the variable range f the maximal and minimal athermatus invlvement nted at each measurement pint. Hwever, segments with greater calcificatin tended t have a larger burden f athersclertic plaque, and segments with less calcificatin tended t have less athersclertic plaque. Althugh it was ur hypthesis that crnary artery calcium burden defined by ultrafast cmputed tmgraphic. scanning was a direct result f the presence f crnary artery athersclertic plaque, it is f ptential clinical interest t cmpare crnary calcium burden with individual percent crnary lumen area stenses. The relatin between the percent area stensis fund fr each crnary segment and the crrespnding amunt f crnary artery calcificatin was determined. Fr all 522 crnary artery sectins, the crnary calcium burden at any pint in the artery was quantified and pltted against the crrespnding percent area stensis fund n histlgic examinatin f the same crnary segment. Figure 5 shws the percent area stensis versus the crrespnding number f vxels with a cmputed tmgraphic number > 130 representing crnary artery calcificatin. Here a quadratic curve fit fr all crnary segments was determined as suggested by review f the data. Similar t the results fund when pltting crnary calcificatin versus plaque area, a direct and psitive relatin was fund between the amunt f calcificatin detected by cmputed tmgraphy and the percent area lumen bstructin by athersclertic plaque. Highly calcified segments have a high likelihd f ttal r near ttal crnary cclusin, althugh there is cnsiderable spread within the data. Hwever, segments with n bvius tmgraphic calcificatin (that is, calcium burden = 0) displayed a wide range f athersclertic narrwing.

6 Nvember I. 1992: SIMONS ET AL A. Frequency f Observatin ('Y) 35.-~~ ~ PERCENT LUMEN AREA STE:-.'OSIS AVERAGE STE:-.'OSIS 9 MAXI~IAL STE:-.'OSIS IL ~ 60..::: I 62% -I-."~'~ I :: 10 5 B Percent Lumen Area Stensis OL- -L =- -J LAD LCX RCA CORONARY VESSEL Figure 7. Analysis f the crrespnding percent lumen area stensis within any sectin f a given crnary artery when the vessel as a whle failed t demnstrate crnary calcificatin n ultrafast cmputed tmgraphic scanning. Data are presented as the maximal and mean crnary stenses f all segments within the respective crnary vessels. LAD = left anterir descending, LCX = left circumflex and RCA = right crnary artery. 75 '" >75'" Percent Area Lumen Stensis 2.5% Figure 6. A, Frequency distributin f nn calcified segments by ultrafast cmputed tmgraphic examinatin and the assciated percent lumen area stenses by decade. The mst frequently ccurring crnary lesin is apprximately 20% t 30% lumen area stensis. B, Cumulative frequency distributin f nncalcified segments by ultrafast cmputed tmgraphic examinatin and the assciated percent lumen area stenses fr thse segments displaying <75% and <':75% stensis. Nearly 98% f all crnary segments that failed t display detectable calcificatin by cmputed tmgraphy were assciated with nnbstructive disease. T further analyze the relatin between 110 crnary artery calcificatin as detected by ultrafast cmputed tmgraphic scanning with the crrespnding athersclertic lumen area bstructin, data were analyzed n a segmentby segment and vessel by vessel basis. In ttal, f the 522 paired cmputed tmgraphic and histlgic sectins, 331 (63%) were fund t have n detectable crnary artery calcificatin frm the tmgraphic analysis. Fr this set f scans, perfrmed under "ideal" scanning circumstances, crrespnding histlgic lumen crss-sectinal stenses ranged frm 0% t 99% (Fig. 5). Thus the absence f crnary calcium by cmputed tmgraphy at a single anatmic site did 1I0t imply the absence f crrespnding histlgic crnary artery disease. Figure 6A shws the frequency distributin f lumen area stenses in the nn calcified crnary artery segments. The mde f this distributin suggests that the mst frequently bserved percent lumen area stensis was between 20% and 30% fr these nncalcified segments, a value that wuld crrespnd t minimal disease (diameter stensis <20%) n rutine crnary angigraphy. The majrity f clinical investigatins cnsider that stenses f :550% diameter narrwing are nnbstructive (that is, nt "hemdynamically" significant). Assuming a circular crss sectin, this level f stensis crrespnds rughly t an area stensis f :575%. Figure 6B shws the frequency distributin fr these nncalcified crnary artery segments expressed as representing histlgic measurements f <75% r?75% area stensis. In this case, 322 (97.5%) f the segments fund by ultrafast cmputed tmgraphic scanning crrespnded t segments with n histlgic evidence f bstructive crnary artery stensis. Only eight segments (2.5%) had disease representing?75% area stensis. Analysis f nncalcified crnary segments was extended t include whle crnary vessels that failed t shw any calcificatin by ultrafast cmputed tmgraphic scanning. A ttal f 15 (38%) f the crnary vessels fit this criteria (4 left anterir descending, 7 left circumflex and 4 right crnary arteries; Fig. 7). Here, ifn detectable crnary calcificatin was fund by cmputed tmgraphic scanning f an entire crnary vessel, n bstructive crnary disease culd be fund at histlgic sectining. Crnary disease, if present, was minimal. The previus results and graphs presented the evaluatin f crnary artery calcificatin and athersclertic plaque burden as cntinuus variables. T further elucidate the relatin between the presence f crnary artery calcificatin by ultrafast cmputed tmgraphic scanning and the presence r absence f ally crnary artery disease, further analysis was perfrmed. The histlgic sectins with an assigned stensis scre f 0 (that is, n bvius crnary athersclersis) were paired with the crrespnding cm-

7 1124 SIMONS ET AL. Nvember I. 1992: puted tmgraphic scans t determine the number f "true negative" results (calcium burden = 0) and "false negatives" (calcium burden> 0). Tw hundred frty-tw f the 522 ttal samples were assigned histlgic grade 0 disease and 280 histlgic grade ~ 1 disease (41 = grade 1, 121 = grade 2, 73 = grade 3, 45 = grade 4). Thus the verall prevalence f histpathlgic crnary artery disease in the grup examined was 54%. Table I shws the 2 x 2 cntingency table fr the presence f any histpathlgic crnary artery disease as defined by the absence r presence f crnary artery calcificatin detected by ultrafast cmputed tmgraphic scanning (n = 522). The sensitivity and specificity were 59% and 90%, respectively; the negative predictive value was 65% and the psitive predictive value was 87%. Discussin Relatin between ultrafast cmputed tmgraphic imaging results and histlgically defined crnary artery disease. The bjective f ur study was t investigate the relatin between crnary artery calcificatin as detected by ultrafast cmputed tmgraphic scanning and histpathlgic crnary artery disease. The results frm this human pathlgic study can be used t cnclude the fllwing regarding the definitin f crnary artery calcificatin by ultrafast cmputed tmgraphic imaging and the crrespnding extent f histlgically defined crnary artery disease. 1. The crnary artery calcium burden defined by ultrafast cmputed tmgraphic scanning and the quantitative extent f crnary artery athermatus plaque are directly crrelated. In general, the mre extensive the calcium burden, the mre extensive the athermatus invlvement f the crnary artery segment. Hwever, the distributin f crrespnding plaque areas at a given measured calcium burden was substantial, making tenuus the applicability f this measurement n a segment by segment basis. 2. Fr the majr epicardial crnary vessels, the crrelatin f calcium burden measured by ultrafast cmputed tmgraphic scanning with percent lumen area stensis is highly significant; hwever, by analgy t plaque burden, the results are nt readily applicable n a segment by segment basis. 3. The ttal absence f any crnary artery calcificatin Table 1. Cntingency Table Cmparing Histlgic Detectin f Any Crnary Artery Disease in a Sectin with Ultrafast Cmputed Tmgraphic Detectin f Crnary Artery Calcificatin in That Sectin Crnary Calcificatin by Ultrafast Cmputed Tmgraphy Present Absent Histpathlgic Crnary Artery Disease Present Chi square = 135, p < See text fr details. Absent within a given crnary artery segment by ultrafast cmputed tmgraphic scanning des nt cnfirm the absence f crrespnding crnary artery athermatus plaque, but the mde f the distributin suggests that the mst frequently bserved athersclertic invlvement crrespnds t minimal crnary artery disease. Hwever, the tmgraphic absence f detectable crnary artery calcificatin is highly predictive f the absence f bstructive crnary artery disease (that is, n area stensis ~75%) n a segment by segment (negative predictive value 97.5%) and a vessel by vessel (negative predictive value 100%) basis. 4. When predicting the presence f any definable crnary artery calcificatin by ultrafast cmputed tmgraphic scanning with the presence f any athersclertic plaque within any given segment f the crnary arteries, the verall sensitivity and specificity were 59% and 90%, respectively. The psitive predictive value f tmgraphic crnary calcificatin and any crnary artery disease in the present study was 87%, whereas the negative predictive value was 65%. Finally, definitin f the ttal cardiac as well as the individual crnary artery calcium burden is virtually identical whether ultrafast cmputed tmgraphic scanning is perfrmed under "ideal" (transaxial) cnditins r under cnditins cnsistent with clinical image acquisitin (that is, imaging f the heart as a whle). Applicatin f ultrafast cmputed tmgraphy t definitin f crnary artery disease. Athersclertic crnary artery disease is ne, if nt the leading, cause f mrbidity and mrtality in industrialized natins. Early detectin may benefit the ppulatin in general but may be especially useful in subgrups f patients at high epidemilgic risk fr mycardial infarctin r sudden death wh are asymptmatic at the time f initial evaluatin. Detran and Fre Iicher (14) summarized current methds f screening fr crnary artery disease. The rest ECG is readily available and inexpensive but is useful primarily t detect intercurrent ischemia r infarctin, r bth. ST segment abnrmalities are nly slightly mre sensitive than are Q waves, but their presence is nt sufficiently specific fr effective screening. Treadmill exercise testing has an average sensitivity f 65% with a specificity f 85% in detecting flw-limiting crnary artery disease. The average sensitivity fr thallium stress testing fr any vessel disease is 84% with a specificity f 87% (15), but these results are highly dependent n the incidence f disease in the patient grup examined. Exercise testing is mst helpful in symptmatic men ver the age f 55 t 60 years and is least helpful in yung wmen with atypical angina. Hwever, current methds f screening fr crnary artery disease can nly detect athersclertic plaque when a sufficient amunt is present t impede crnary artery flw r flw reserve. Nnbstructive crnary lesins are generally undetected by traditinal treadmill r pharmaclgic stress testing. Three pstmrtem studies (3-5) have shwn that crnary artery calcific depsits arc bth sensitive and specific fr predicting the presence f crnary athersclersis. Fr

8 Nvember I. 1992: SIMONS ET AL clinical applicatins, flurscpy was first used t detect crnary artery calcificatin; althugh it is highly specific, it lacks sensitivity because f verlapping structures and lw reslutin (14). Agatstn et al. (8) recently used ultrafast cmputed tmgraphic scanning t detect and quantify crnary artery calcium burden in patients with and withut crnary artery disease. They cncluded that in patients with disease (a histry f mycardial infarctin r dcumented angigraphic lesins f >50% lumen diameter stensis), this tmgraphic technique had a high sensitivity f detecting crnary artery calcificatin, which was significantly better than that f flurscpy (90% vs. 52%, respectively); additinally, the negative predictive value f a calcificatin scre f 0 and n crnary artery disease was high. The absence f crnary artery calcificatin detected by ultrafast cmputed tmgraphic scanning may allw identificatin f a subset f patients wh have an underlying llv risk f develping subsequent cardiac events. Cnversely, the presence f such calcificatin and its relatin t athersclertic plaque may allw fr a nninvasive means t fllw the prgressin r regressin f anatmic crnary artery disease. Lipid-lwering therapy r ther risk factr mdificatins culd then be directed tward a grup f patients wh may be at higher risk and benefit mre frm this interventin than wuld the general ppulatin. In the current study, nly 2 (15%) f the 13 patients had an antemrtem diagnsis f crnary artery disease despite the >50% prevalence f histlgic crnary artery athersclersis in the ppulatin studied.. Studies such as thse f Agatstn and clleagues (8) prvided imprtant data n the ptential clinical applicability f ultrafast cmputed tmgraphic screening fr crnary artery disease and n the epidemilgy f crnary artery calcificatin. Our study indicates the direct relatin f crnary calcificatin t disease and helps t define the abslute limits f any clinical applicatin f the ultrafast cmputed tmgraphic methdlgy. Our results shw that crnary calcificatin as detected by this technique is highly predictive f the presence f histpathlgic crnary artery disease, but the amunt f calcificatin present has limited applicatin in determining the in situ degree f athersclertic invlvement. Cnversely, the absence f any crnary calcificatin n a segment by segment and vessel by vessel basis is highly predictive f the absence f anatmically significant crnary artery disease. Ultrafast cmputed tmgraphic screening may eventually prve t be a mst effective nninvasive methd t detect anatmic crnary artery disease r t rule ut the presence f critical disease in humans. Hwever, althugh the present results are encuraging, lng-term clinical studies are needed befre the significance f crnary artery calcificatin detected by ultrafast cmputed tmgraphic scanning and its natural histry are knwn. Screening fr crnary artery disease with this tmgraphic technique shuld nt be widely emplyed until such studies are cmpleted. Majr questins need t be answered regarding the apprpriateness f general screening fr crnary artery disease because the ttal absence r the presence f a small amunt f crnary calcificatin des nt necessarily imply the absence f disease r the presence f "significant" disease, respectively. Only carefully perfrmed epidemilgic investigatins will establish the applicability f this methdlgy t identificatin f clinical crnary disease. Limitatins f the study. There are several limitatins f the current study. First, a single 5-Jlm histlgic sample t quantify the extent f crnary artery disease in a 3-mm thick tmgraphic sectin can be questined. Limitatins f the imaging methd at present d nt allw fr thinner direct tmgraphic sectining, althugh a I-mm helical scanning prtcl is under develpment. Nevertheless, it is assumed that direct cmparisns can be determined because the presence f crnary calcificatin implies crnary plaque smewhere within that crnary segment. Sme sampling errrs are t be expected, but effrts t be cnsistent were made thrughut the study. The actual in situ extent f crnary artery calcificatin and the amunt detected by ultrafast cmputed tmgraphic scanning may nt be identical. Direct cmparisns between histlgic crnary artery calcium cntent and tmgraphic calcium burden need t be perfrmed. In the current study, all crnary specimens were decalcified befre histlgic preparatin, as is standard in mst pathlgy labratries, t allw fr ease f micrtme sectining. Methds are underway in ur labratry t allw fr prper sectining f specimens that are nt decalcified by using techniques develped in bne histmrphmetry. The chice f 130 H fr a threshld was intended t mimic the value used in the prir clinical study by Agatstn et al. (8). Nncntrast-enhanced mycardial tissue density by cmputed tmgraphy is apprximately 35 t 55 H. A higher value fr the threshld fr crnary calcificatin as any discrete density abve the 130 H used in the current study might have increased specificity but prbably wuld have reduced sensitivity; the cnverse wuld be true if a lwer threshld value were used. When viewed n the display screen, the areas f crnary artery calcificatin are almst always quite bvius within the tmgram (Fig. I and 2). Fr the present, the threshld f 130 H is cnsidered t be a reasnable value, being at least tw t three times greater than the maximal density f nn cntrast-enhanced mycardial tissue. Additinal statistical analysis using receiver perating characteristic curves are required t examine the effect f variable threshld n sensitivity and specificity. Hwever, this type f analysis is nt pssible with the available image prcessing sftware. Additinally, variable patient bdy habitus may alter the cmputed tmgraphic attenuatin such that a prper threshld in clinical practice may be greater r less than the single value f 130 H used in the current investigatin. Mre clinical wrk is necessary t determine the threshld r threshlds that prvide the greatest clinical utility. Cmparisns between histlgic findings and cmputed

9 1126 SIMONS ET AL. lacc Vl. 20. N.5 Nvember I. 1992: tmgraphic results were made nly during the final data analysis; thus the results f the histlgic analysis were btained withut knwledge f the results f the cmputed tmgraphic analysis. The sftware emplyed required placing an peratr-defined regin f interest arund the vessel and defining the number f vxels with a cmputed tmgraphic density ;:: 130 H. Fr each sectin examined, the results were exactly reprducible; thus there was n inter- r intrabserver variability fr the cmputed tmgraphic analysis. The relatin between paired cmputed tmgraphic and histlgic samples may have been cnfunded in that experimental errr culd have allwed a slight discrdance between the 3-mm cmputed tmgraphic scan and the amunt f calcificatin and the crrespnding histlgic plaque. Areas that were deemed t be nncalcified might have had less disease if this had ccurred. Als, because crnary calcificatin may nt be hmgeneusly distributed within a plaque, a lng lesin that is calcified at ne pint but nt at anther culd be misclassified as a nncalcified lesin assciated with significant athersclersis. Finally, the histlgic sampling was perfrmed at anther site and time frm the tmgraphic sectining by ultrafast cmputed tmgraphy. Minr errrs f misregistratin culd ccur with imprper assignment f ne cmputed tmgraphic sectin with an incrrect histlgic sectin. Again, the histlgic sectining was perfrmed in a cnsistent manner by the same investigatrs (D.B.S., W.O. E.) fr each heart and vessel; thus, cnsidering the large number f samples, minr errrs may be present but shuld nt change the verall utcme. We sincerely thank Allen Camrud, RN fr expert assistance with handling and sampling f the histlgic data, the technlgists wh patiently facilitated the ultrafast cmputed tmgraphic scanning in an excellent and rapid manner during the busy wrkday and Rbert Frye, MD, whse encuragement f the prject and devtin t a meaningful research experience within the internal medicine training prgram is sincerely appreciated. References t. Epstein SE, Quyyumi AA. Bnw RO. Sunding bard: sudden cardiac death withut warning: pssible mechanisms and implicatins fr screening asymptmatic ppulatin. N Engl J Med 1989;321: Little WC. Cnstantinescu M. Applegate RJ. et al. Can crnary angigraphy predict the site f a subsequent mycardial infarctin in patients with mild t mderate crnary artery disease. Circulatin 1988;78: Frink RJ. Achar RW. Brwn AL. Kincaide AW, Brandenburg RO. Significance f calcificatin f the crnary arteries. Am J Cardil 1970;26: Warburtn K. Tampas JP, Sule AB. Taylr HC. Crnary artery calcificatin: its relatinship t crnary artery stensis and mycardial infarctin. Radilgy 1968:91: McCarthy JH. Palmer FJ. The incidence and significance f crnary artery calcificatin. Br Heart J 1974;36: Rit1dn RD, Parisi AF, Hlland E. Crnary calcificatin in the diagnsis f crnary artery disease. Am J Cardil 1979;44: Reinmuller R. Liptn MJ. Detectin f crnary artery calcificatin by cmputed tmgraphy. Dyn Cardivasc Imaging 1987;1: Agatstn AS, Janwitz WR, Hildner FJ, Zusmer NR, Viamnte M, Detran R. Quantificatin f crnary artery calcificatin using ultrafast cmputed tmgraphy. J Am Cli Cardil 1990;15: Feiring AJ. Rumberger la. Skrtn OJ, et al. Determinatin f left ventricular mass in the dg with rapid acquisitin cardiac CT scanning. Circulatin 1985;72:\ Reiter Sl, Rumberger JA. Feiring AI. Stanfrd W, Marcus ML. Precisin f right and left ventricular strke vlume measurements by rapid acquisitin cine cmputed tmgraphy. Circulatin 1986;74: It. Feiring AJ. Rumberger JA. Reiter Sl, Stanfrd W. Marcus ML. Sectinal and segmental variability f left ventricular functin: experimental and clinical studies using ultrafast cmputed tmgraphy. 1 Am Cli Cardil 1988;12: Rumberger la. Weiss R. Feiring AJ. Marcus ML. Patterns f reginal diastlic functin in the nrmal human left ventricle: an ultrafast cmputed tmgraphic study. J Am Cli CardiI1989;14: Rig E. Chmka EV. Castaner A. Brundage BH. Exercise ultrafast cmputed tmgraphy fr the detectin f crnary artery disease. 1 Am Cli CardiI1989;13:1073-8t. 14. Detran R. Frelicher V. A lgical apprach t screening fr crnary artery disease. Ann Intern Med 1987;106: Ktler TS. Diamnd GA. Exercise thallium 201 scintigraphy in the diagnsis and prgnsis f crnary artery disease. Ann Intern Med 1990;113: