Serial Tomographic Imaging with Technetium-99m-Sestamibi for the ...

Serial Tomographic Imaging with Technetium-99m-Sestamibi for the Assessment of Infarct-Related Arterial Patency Following Reperfusion Therapy Wayne St. Gibson, Timothy F. Christian, Patricia A. Pellikka, Thomas Behrenbeck and Raymond J. Gibbons Division ofCardiovascular

Diseases and Internal Medicine, Mayo Clinic, Rochester, Minnesota

fore, there is a need to develop noninvasive techniques to The purposeof this study was to determinethe relationship assess arterial patency, so that l0%—25% of patients cur of changesin the seventy and extent of hypoperfusionon rently discharged from the hospital with a closed infarct serial tomographic

@Tc-sestamibiimages with patency of

related artery despite thrombolytic therapy would not be

the infarct related artery during acute myocardial infarction. deprived ofthese benefits (6). We studied 109 patients with acute myocardialinfarction Technetium-99m-hexakis-2-methoxy

isobutyl isonitnle (sestamibi) is a radiopharmaceutical which accumulates in 18—48 hr later. Perfusiondefect extent and defect area, an viable myocardium in relation to myocardial blood flow. indexof defectseverity,weremeasuredon bothstudies. The minimal redistribution of99mTc@sestamibipermits the Both defect extent and defect area were significantly(p = evaluation of the extent of myocardium at risk in acute 0.0001) greater for anteriorinfarctionsthan for inferiorand lateral infarctions.By two factor analysisof variance, the myocardial infarction without delaying reperfusion ther change in defect area varied significantly with both infarct apy (10). When 99mTc@.@mibi was injected during cor location(p = 0.0001)andpatencyof the infarct-relatedartery onary occlusion in animal models, its uptake correlated using tomographic @“Tc-sestamibi imagingacutely and at

(p = 0.002). The changein defect extent also varied signifi

with microsphere flow, and the defect measured by

@mTc@

cantlywith bothinfarctlocation(p = 0.0001)andwith patency sestamibi correlated closely with the anatomic risk area ofthe infarct-relatedartery(p= 0.004).Inpatientswith inferior (11). When 99mTc@ta@bi was injected after reperfusion, myocardialinfarction,a changeindefectextentor defectarea its uptake was significantly less than microsphere flow; of greaterthan4% or 0.017, respectively, hada positive however, the defect size correlated closely with postmor predictiveaccuracyof 96% and 93%, respectively,for the tem infarct size (11). The change in defect size between identificationof a patent infarctartery.Therefore,sequential occlusion and reperfusion is therefore a measure of treat changeson tomographic @“Tc-sestamibi imagesare of po ment efficacy or myocardial salvage. tential value for the noninvasiveassessmentof patencyof Serial changes on 99mTcsestamibi images are related to the infarct-relatedartery. patency ofthe infarct-related artery. A multicenter trial of J NucI Med 1992; 33:2080-2085 serial planar imaging (12) for the noninvasive assessment of thrombolytic therapy found that patients with a patent infarct-related artery had a significantly greater decrease in defect extent on follow-up images than those with ntervention with thrombolytic therapy in acute myo persistent occlusion. Pellikka et al. (13) reported that early cardial infarction has been shown to reduce mortality in changes in defect extent assessed by tomographic @mTc@ several randomized trials (1-3). A beneficial trend with sestamibi imaging were related to infarct-related arterial primary percutaneous transluminal coronary angioplasty patency. A significant decrease in defect extent occurred has been shown in several non-randomized studies (4,5). in 47% of patients with patent infarct-related arteries The demonstrated reduction in mortality from reperfusion between the initial and 18-48 hr studies. However, in therapy appears to be out of proportion to the reduction patients with an occluded infarct-related artery, no signif in infarct size (6), and is one of several lines of evidence icant change in defect extent occurred. These early studies that suggest that there may be additional clinical benefits had several limitations, including small patient numbers, from an open infarct-related coronary artery (7—9).There the absence of any adjustment for the important effect of infarct location (14) and a failure to consider the severity

of theperfusiondefecton tomographicimaging. ReCeived Feb. 7, 1992; revision accepted Jul. 27, 1992. For reprints

contact:

Raymond

J. Gibbons,

5treet, S.W., Rochester,MN 55905.

2080

MD, Mayo Clinic, 200 First

The purpose of this study therefore was to determine the relationship between changes in both the severity and

The Journalof NuclearMedicine• Vol. 33 • No. 12 • December1992

extent of the perfusion defects seen on serial tomographic imaging with 99mTcsestamibi within 48 hr of acute myo cardial infarction with patency ofthe infarct-related artery.

1Comparison

TABLE

of the Timefrom CoronaryAngiographyto the 18—48 Hr

@“Tc-Sestamibi ReperfusionMethodstTime Studyfor Different

angiographyto from I 8—48 hr @‘Tc

METHODS

StudyGroup

sestamibi (hours)median study.

The study group consisted of a consecutive series of patients enrolled in a prospective study of 99mTc@sestamibi who met the following criteria: I . Chest pain ofgreater

than 30 mm and less than

12 hr onset.

2. Elevatedcreatinephosphokinase (CPK-MB) isoenzyme fraction

of greater

than

5% of the total CPK

within

24 hr

75thReperfusion

(25th,

percentile)Thrombolysis method N 24)Thrombolysis

18

—18)PTCA + PTCA

20

3.5 (—19, —21(—26,

—23)Conventional 61 1)* 10

—31 (—39, —3.5 (—20,

from the onset of chest pain by an electrophonetic method

(15). 3. Coronary angiographyperformed during the present hos pital admission.

4. Tomographic 99mTc..ses@mibi imaging acutely and repeated

within 18—48 hr. There were 134 patients who met the above criteria. Exclusion criteria were: ( 1) evidence of previous myocardial infarction

by history

or electrocardiogram

(23 patients)

and (2)

previous revasculanzation (2 patients). The study group therefore consisted of 109 patients; 25 of these patients were included in a previous study (13).

Electrocardiography ST-segment elevation

0. 1 mV was considered significant.

One hundred and three patients (94%) had significantST-seg ment elevation. The six patients without ST elevation all had occluded infarct-related arteries. ST-segment elevation in two contiguous precordial leads were classified as anterior infarction, whereas changes in leads II, III and aVF were classified as inferior infarction. ST-segment elevation solely in leads I and aVL was

classifiedas lateral infarction. For the six patients without ST segment elevation, infarct location was determined from the regional wall motion abnormality on contrast ventriculography and/or the perfusion defect on tomography. Reperfusion Therapy

The four methodsof reperfusionwere:(1) intravenousthrom bolysis,(2) primary coronaryangioplasty,(3) thrombolyticther apy followed by coronary angioplasty within 24 hr and (4) con ventional treatment without reperfusion therapy. Further details are provided in Table 1.

1 8—48

hr

@“Tc-sestamibi

study

is

taken

as

time

0.

A tomographic radionuclide acquisition was performed within

6 hr ofeachinjectionwith thepatientsupineandwith theuseof a rotating single-headedgamma camera (Elscint, Haifa, Israel). Thirty images (64x64 matrix) were acquired for 40 sec each, every 6°over an I800 arc, beginning in the 45°right anterior oblique position and ending in the 45°left posterior oblique.

Images were reconstructed with standard backprojectional gorithms and a Ramp-Hanning filter. Short-axis slices of the left ventricle were reconstructed every 6 mm, with subsequent nor malization to the peak counts in the heart for each set of images. Peak counts in every 6°sector around the left ventricle were identified for representative apical, midventricular, basal and two intermediate slices (midway between the apex and the midven tricle and midway between the midventricle and base). Circum ferential

count

profiles

were generated

in which

each pixel was

normalized by the peak value in the profile. Quantification of the extent of hypoperfusion was performed using a previously de scribed method (1 7). A threshold value of6O% ofthe maximum pixel value in each of the five circumferential count profiles was

used to determine the defect extent, which was expressedas a percentage of the left ventricle. This method has been validated in cardiac phantom studies, where the measured defect and true defect closely correlated (r = 0.99) (18). A similar technique in an animal model yielded excellent agreement with histologic infarct

size (r = 0.95) (19).

Defect severitywas estimated on each profile by integrating

with the method of reperfusiontherapy (Table 1). The infarct

the area of the profile that was less than 60% of the maximum pixel value (Fig. 1). The total defect area was computed as the sum ofthe areas from the count profiles ofthe five representative slices, adjusted for the radius of each slice using the same as sumptions employed in the calculation ofthe defect size (18). The change in the defect area was calculated as the difference in the defect area from the acute to the 18—48hr study. The change in defect extent was also calculated from the acute to the

related

18—48hr study (Fig. 2).

Coronary Angiography All patients underwent coronary angiography during the pres

ent admission.This was generallyperformedwithin one day of the 18—48 hr sestamibi study, although the time interval varied artery

was identified

by analysis

of the initial

ECG

ST

segmentchanges,the site of regionalwall motion abnormalities Statistics on left ventriculographyand the coronaryangiogram. Patency was defined as Thrombolysis in Myocardial Infarction

(TIMI) Grade II or III; occluded infarct-relatedarteries were defined by (TIM!) Grade 0 or I (16).

Radionuclide Studies

Data are presented as mean values ±s.d. Differences between paired data were analyzed by a paired Student's t-test. The variation ofthe time to reperfusion therapy with infarct location was analyzed using a one factor analysis of variance. Infarct location

and arterial

patency

were entered

as independent

vari

nously in all patients during acute myocardial infarction before initiation of reperfusion therapy and again 18—48 hr later.

ables in a two factor analysis of variance (ANOVA) to examine their effect on the extent and severity ofthe perfusion defect and the change in both parameters from the acute to 18—48 hr study.

SerialTomographicImagingwith Sestamibi• St. Gibsonet al

2081

Technetium-99m-sestamibi

(20-30

mCi) was injected

intrave

Of the 17 patients with an occluded infarct-related artery, 11 had inferior infarctions, 3 had lateral infarctions and 3

1.0

had anterior infarctions. The time to reperfusion therapy was significantly longer for patients with anterior infarc tions compared to those with inferior and lateral infarcts

C

8

4

Extent

0.6

(p = 0.05). Approximately 66% of patients with lateral infarctions had residual stenosis ofgreater than 90% com pared to 28% with inferior and 4% with anterior infarction. Details of these two groups are provided in Table 2.

1@ 0

90 Iater@

0

180 inferior

270

360

septal

anterior

Degrees

Effect of Infarct-Related Arterial Patency

The effect of infarct-related arterial patency on both the extent and area of the perfusion defect was analyzed after controlling

for the effect of infarct location by the two

factor analysis of variance (Table 3, Fig. 3). The change in FIGURE 1. Representative midventricular circumferential pro defect extent from that measured acutely to that measured file. The defect area was calculatedfrom the circumferential at 18—48 hr was significantly greater for patent infarct profile curve for each of the five slices. The defect area is the summationof pixelslessthan60%the maximumcurvevalue. related arteries compared with occluded infarct-related Forallpixels,P,suchthatP< 0.6 x maximumcurvevalue: arteries (p = 0.004). The change in defect area was also Area =

significantly greater for patent infarct-related

@O.6 —_____________

max@curve value

Hencethe defectareais a dimensionless unit and reflectspn manlytheseverityof hypoperfusion. RESULTS

StudyGroup The study population consisted of 89 men and 20 women. The mean age was 60 ±12 yr (range 28 to 87). There were 92 patients with patent infarct-related arter ies and 17 patients with occluded infarct-related

arteries com

pared with occluded infarct-related arteries (p = 0.002).

arteries.

Effect of InfarctLocation The effect of infarct location on defect extent was ana lyzed after controlling for the effect of infarct-related ar terial patency by the two factor analysis of variance. The defect extent acutely, and at 18—48 hr and the change in defect extent varied significantly with infarct location (p =

0.0001).

The defect area measured acutely at 18—48 hr later and the change in defect area varied significantly with infarct

;;•,@aC,‘I

FIGURE2. Representative (A)basalshort-axis slices,(B)mid-ventricular short-axis slices,(C)secondsliceshort-axis slicesand (0) horizontallong-axisslicesfroma patientwithacuteanteriorinfarction.Theimageontheleftineachpanelis acute;theimageon therightis at 18—48 hr.Thereis a largeinitial,anterior,septalandapicalperfusiondefectthatsignificantlyimproves.Thechangein defectextentwas62%;thechangeindefectareawas0.29.

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TheJournalof NuclearMedicine• Vol. 33 • No. 12 • December1992

DISCUSSION

TABLE 2

ClinicalCharacteristicsof the StudyPopulation LocationsSubgroupedInfarct Accordingto Infarct InferiorLateralN location 566Time to therapy(min) 71.5Residual

@90%(No. stenosis (28%)4(66%)Patent of patients)

These results indicate that perfusion defect extent and severity on early serial quantitative 99mTc..sestamibito mographic imaging are related to both infarct location and patency of the infarct artery. The difference in defect

Anterior 47 364 ±301

2 (4%)

453Occluded

237 ±138183.5

±

severity and extent assessed acutely and 18—48hr after

reperfusion therapy was significantly greater in patients with a patent infarct-related artery and in patients with anterior infarction. The determination of the patency status of the infarct related artery following reperfusion therapy is of clinical value. Animal studies have demonstrated that late reper fusion of an occluded infarct-related artery, may reduce

16

44

113Reperfusion

3

therapyr-t-PA 121SK 11PTCA

3 0

241r-t-PA 120Conventional + PTCA therapy

36 8 0

location after controlling

infarct expansion

73

for the effect of infarct-related

arterial patency (p = 0.0001). Prediction of the P@tencyStatus of the Infarct Artery

The small nur icr of patients with occluded infarct related arteries . .1idanterior or lateral infarction precluded further analysis of these groups. For patients with inferior infarctions, the median change in defect extent and defect

without reducing infarct size (7). The

beneficial effects of a patent infarct-related artery on late ventricular arrhythmias has been demonstrated in animal models to be independent of the recovery of ventricular function (8). The incidence ofventricular tachycardia and subsequent sudden cardiac death was reduced in patients treated with thrombolytic therapy, despite a similar degree of left ventricular dysfunction (9). Mortality benefit is apparent in subgroups ofpatients who achieve reperfusion at a time when myocardial salvage would not be expected (20). These

findings

point

toward

a beneficial

effect of a

imaging concurred with a patent infarct artery in 25 of 26 patients (positive predictive accuracy 96%). A change in

patent infarct-related artery on electrical instability in ad dition to a reduction in infarct size. The assessment ofthe efficacy ofreperfusion therapy by serial quantitative planar @mTc@sestamibi imaging in acute myocardial infarction was reported by Wackers et al. (12).

defect extent of less than 4% concurred with an occluded

The initial myocardium

artery in 10 of 30 patients (negative predictive accuracy 32%). A change in defect area of greater than 0.017 con

patients prior to reperfusion therapy, with repeat imaging at 18—48 hr and 6—14 days. Patients with a patent infarct related artery had a significantly greater decrease in defect extent than did patients with persistent coronary occlusion

area were 4% and 0.017, respectively. A change in defect extent of greater than 4% of the left ventricle on serial

curred with a patent infarct artery in 25 of 27 patients (positive predictive accuracy 93%). A change in defect area ofless than 0.017 concurred with an occluded infarct artery

at risk was determined

in 30

(—51 ±38% versus —1±26%, p = 0.0001). In our study,

in 9 of 29 patients with such a change (negative predictive

the change in defect extent was significantly greater for

accuracy 3 1%). This is illustrated in Figure 3.

patent infarct-related

arteries after controlling for the effect

TABLE 3 Comparisonof the Extent and Severityof Hypoperfu@ed Myocardiumwith the PerfusionStatus of the Infarct-RelatedArtery

for DifferentInfarctLocations p*Infarct-related vs.

arterystatus

InfarctlocationPatentOccludedInfarct occludedAnteriorInferiorLateralAnteriorInferiorLateralNumber

locationPatent

13Defect of patients4445331

LV)Acute50±1418±1135±2119±414±9.534±280.00010.0118—48hr31.5±2012±1014±2515±12.514±7.530±220.0001nsChange18±1 size (%

areaAcute0.194

0.120.00010.0318—48 ± ±0.080.05 ±0.0440.128±0.120.042 ±0.0370.033 ±0.0320.13 0.1070.0001nsChange0.098 hr0.096 ±0.090.023 ±0.0260.060 ±0.100.025 ±0.0330.028±0.0230.121 ± 0.0250.00010.002* ±0.0680.027±0.0300.070±0.0500.003±0.0290.005±0.0270.010± By

two

factor

analysis

ofvariance(ANOVA).

SerialTomographicImagingwith Sestamibi• St. Gibsonet al

2083

A

on the reperfusion method used. This high pretest proba

014

bility for infarct arterial patency contributes

0 12 Cs

!

Cs

@

Oi 008

@

006

.c

thrombolytic

0.04

@) 002

0

0

19 patients with a patent infarct-related

@0 02

Patent

Ocduded

IRA Infarct-related arterial status

location

B

@20 Cs

io

C

Cs

0-

-C

-10

a)

0

at risk, final infarct size, and

with inferior infarctions following successful reperfusion

30

Cs

•0

on myocardium

myocardial salvage. They reported a significantly greater change in defect extent with anterior infarctions compared

C

6)

artery, 9 demon

strated a significantly reduced defect extent at 18—48hr. However, the influence of infarct location on the magni tude of change in defect extent was not considered. Christian et al. (14) reported on the effect of infarct

-004

@

therapy were reported by Pellikka et al. (13).

In six patients with an occluded infarct-related artery, there was no significant change in defect extent at 18—48 hr. Of

Cs Cs .C

to the low

negative predictive accuracy of serial tomographic @mTc@ sestamibi for the identification ofoccluded infarct arteries. The early changes in perfusion defect extent following

-20

—

11@I

@i

.@l'{

Patent

Occluded

IRA

Infarct-relatedarterial status

FIGURE 3. Scatterdiagramsof the changein (A)defectarea

therapy. However, no significant change in defect extent was noted in patients with an occluded infarct-related artery. In the study by Christian et al., imaging was per formed prior to hospital discharge (6—14days postinfarc tion) in contrast to early imaging at 18—48 hr in our study. Our results at 18—48hr confirm the influence of infarct location on the change in defect extent. Similar to Chris tian et al., we did not find a significant change in defect extent in patients with an occluded infarct-related artery.

and (B) defectextent as a functionof infarct-relatedarterial Clinical Implication patencyfor patientswithinferiorinfarctions. Serial 99mTc@mibi imaging may be of value in the management of acute infarct patients undergoing throm bolytic therapy. Following successful thrombolytic ther of infarct location. This study differs from the study of apy, angiographic reocclusion may be documented in ap Wackers et al. in several respects. First, the effects of infarct proximately 24% ofpatients (22). First, serial tomographic location on the magnitude of change was not accounted imaging with 99mTcsestamibi may be of value in detecting for by Wackers et al. Second, planar imaging was used in silent reocclusion of the infarct artery. A large change in the study of Wackers et al. In contrast, tomographic im defect extent or defect area on imaging at 18—48 hr, which aging, used in this study, is less affected by the overlap of is lost on further imaging at 6—14days, would identify a normal and abnormal areas and has been demonstrated subgroup ofpatients in whom patency ofthe infarct artery to more accurately determine infarct size (19). Third, the has not been maintained and who would benefit from defect integral used by Wackers et al. as a measure of coronary angiography and further interventional therapy. defect extent reflects both the extent and severity of the Second, it is our experience at the Mayo Clinic that serial perfusion defect. In our study, defect extent and severity imaging may assist in the clinical decision as to the urgency were measured separately. of coronary angiography. Patients who demonstrate large A large change in defect extent or severity is highly changes in defect extent and defect area on serial imaging predictive of patency of the infarct-related artery. How who later experience a recurrence of symptoms are more ever, a small change may occur with either a patent or an likely to have urgent coronary angiography than patients occluded artery. This finding is not surprising. First, there who demonstrate negligible changes. Third, serial imaging is an inherent limitation of serial 99mTcse@mibi imaging with 99mTc@tamjbi may be of value in the selection of in the identification of patent coronaries as this agent is the radioisotope for predischarge stress testing. No change not taken up and retained in necrotic myocardium. There or a small changein the extent and severity of hypoper should be little or no retention of @mTc@setamibi in the fusion on serial imaging may be secondary to either a myocardium, if it is already irreversibly damaged at the persistently occluded or severely stenosed infarct artery or time the infarct-related artery is opened by thrombolysis irreversible myocardial damage prior to reperfusion ther or angioplasty. Thus, there may be little change in defect apy. Thallium with redistnbution/reinjection imaging extent or defect area despite a patent artery. Second, the may be preferable for demonstrating viable myocardium probability of infarct-related arterial patency following in patients with resting hypoperfusion (23), since there is reperfusion therapy is greater than 80% (21), depending minimal redistribution of sestamibi. Approximately 30%

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The Journalof NuclearMedicine• Vol. 33 • No. 12 • December1992

ofthe patients who received reperfusion therapy had resid ual stenosis 90%. Limitation This study was limited by the small number of patients with an occluded infarct-related artery. The majority of patients with an occluded infarct-related artery had inferior infarctions with small areas of jeopardized myocardium.

The most likely reason for this finding is the aggressive use of coronary angioplasty and intravenous heparin in our institution,

particularly

when the responsible

at risk. Coronary angiography and the 18—48-hr99mTc injection

were not performed

limitations

8.

9.

10.

simultaneously.

Hence, it is possible that the perfusion status of the coro nary artery might have changed during this period. Potential

7. Hale

physician

was aware that there was a large amount of myocardium sestamibi

ofcoronary angioplasty without antecedent thrombolytic therapy for acute myocardial infarction. Am J Cardiol 1989;64:122l—1230. 6. Ca1IfTRM,Topol EJ, Gersh 53. From myocardial salvage to patient salvage in acute myocardial infarction: the role of reperfusion therapy. J Am Coil Cardiol 1989;l4:l382—l388.

of our quantitative

method,

11.

in

eluding cardiac motion, nonuniform myocardial thickness and the use ofa geometric model ofthe myocardium have been discussed previously (1 7). The quantitative method

12.

will tend to slightly overestimate the extent of anterior

13.

defects because the anterior myocardium is closer to the chest wall and subject to less attenuation and scatter (17, 18). Despite

these limitations,

the measurement

of infarct

size by this method has been shown to closely agree with histologic infarct size in animal models (11,19). These data demonstrate the potential value and limitation of sequential

changes on serial tomographic

imaging with

14.

15. 16.

99mTcsestamibi for the noninvasive assessment of patency of the infarct-related artery.

17.

ACKNOWLEDGMENT

18.

Supported in part by a grant from E.I. DuPont de Nemours

and Company.

19.

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