1282 JACC Vol. 24, No. 5 November P. 1994:KXL9
PIER FILIPPO FAZZINI, klD”
under baseline m~ditions and during isosorbide di~it~te
In patients with chronic coronary artery disease and left ventricular dysfunction the detection of viable hi~rn~ting m~~rdium in asynergic territories is important for indicting their functional outcome after revascularization (1,2). The recognition of a significant ~streva~ularizakion functional improvement in asynergic territories is the true reference standard for establishing the presence of hibernating myocar- dium. Therefore, it is also the most reliable way to test the
aecuracy of diagnostic methods used to evaluate myocardial viability. At present, the detection of an intact glucose metab-
olism in hypoperfused areas (perfusion/metabolism mismatch) by positron emission tomography is considered the most reliable imaging method for assessing myocardial viability
,F? the Nuclcur Medicine Unit. Department of Clinical PathophysioloK
;Jrsty of Florence and ‘Divkion of Cardiology, Careggi Hospifal, Florence. _*
-Manu L%pt received Nwember IO,1993 revised manuscript received May 9, 1994 aecepxd June L 1994.
: Dr. Gianni Bisi, Nuclear Medicine Unit, Department of Clinical Pathophysiology, University of Florence, Viale Morgagni 85, SO134 Flonr102, Italy.
8 t9%4 hy the American College of Cardiology 773%1097/94/$7.00
(3-5). However, the most widely used metbo
tion of thallium-201 uptake using late redistribution or rest injection imaging (6-11). Although both methods are effective, they have important limitations. positron emission tomography is expensive and confined to relatively few laboratories. Thallium-201 is not as reliable as positron emission tomogra- phy, mainly because of false negative results (4,5).
Several experimental studies (12-21) have demonstrated that the features of technetium-99m sestamibi are favorable for its use as a viability tracer. However, other reports (22-27) have suggested that in humans, rest technetium-99m sestamibi underestimates the extent of viable myocardium compared with positron emission tomography and thallium-201 imaging. More specifically, two studies (26,271 have suggested that segments with abnormally low technetium-99m sestamibi up take may recover function after revascularization. However, taking technetium-99m kinetics into account, it is eivable that interventions capable of increasing coronary during the tracer uptake could improve its detection of viable myo- cardium. Several reports (28-38) indicate that short-term nitrate administration increases coronary flow by means of
JACC Vol. 24, No. 5 BlSl EF AL.
November 1. 1994:1X!-“, NITRATE TECHNETUJM-Wm SESTAMlBl IMA~XW 1283
s. It has been also de
P uptake
in
hypoper-basis
of
their clinical condition, ilded nitrate therapy for at least 48 h before the beginning of the study. Ali other apies were continued, and the dition of the natients ained unchanged until the st was completed. The the execution of ~vo-~inlensional echocar- diograpby to assess regional wall motion and hvo technetium- 99m sest;mibi studies, one at baseline conditions aad the other after short-term administration of isosorbide dinitrate. During technetium-99m sestamibi injection for baseline scintigraphy, first-pass radionuc~ide angiocardiography was acquired to es- timate global left ventricular function. T
studies were performed in ran om sequence, 24 h apart, after overnight fasting. Ali patient nderwcnt coronary angiogra- phy within 2 weeks of the scintigraphic studies. Global and regional left ventricular function were again assessed with first-pass radionuclide angiocardiography and two-dimensional echocardiography, respectively, at least 3 months after the execution of coronary artery bypass grafting or at least 1 month after coronary angioplasty. All patients gave informed consent to participate in the study. The study protocol was approved by the ethics committee of our institution.
Coronary an&graphy. Selective coronary angiography was performed using the Judkins or Sones technique. Cinean- giograms were evaluated on the basis of the agreement of two observers who had no knobledge of the clinical and scinti- graphic data. Lesions that reduced lumen diameter ~50% were considered significant. Collateral circulation was assessed and scored in four grades (collateral index) from 0 = none to lete filling of the epicardial vessel through collateral flow (38,41).
Echocardiography. Two-dimensional echocardiography was performed using an Aloka SSD-870 echocardiograph with 2.5- to 3.5~MHz transducers. Parasternal long-axis, parasternal
rni~ventr~c~~a~ levels and views were o~~a~~~~ and ventricle was divided into 13
segments ~ante~~sept~~, anterior, anterolateral, posterolateral, ste~~media~, posteroseptal) were evaluated both at a basal
mi~ventric~~a~ level in ~~d~iion to a single apical segment. Seven segments were attributed to the left anterior descending coronas, two to the left circnm ex coronary artery and four a0
ght coronary artery.
otion was visually analyzed by two in d no knowledge of clinical, ang ings. The following scoring sy
hypokinesia (clearly reduced systolic wall thickening and inward motion); 3 = akinesia (absence of systolic wall t~~~ckening and motion); 4 = dyskinesia (sy Wall ~~1~~~I~j~~ and outward motion). A segment was cidssi
cast 50% of its total area exhibited abnormal le wall motion index was cakulated for each
as the sum of the scores of all the included scgmcnts divided by the number of segments (43). repan-
d~onnc~ide angiocard~ogra~~~y was acquired in the 30” right projection with the patient supine, using an gamma camera equipped with a low energy all-purpose collimator and using a 20% window CP
140-keV photopeak of technetium-99m. Twenty- ies (925 ABET of technetium-99m sestamibi
through an indwelling cannula inserted into an antecubital vein of the right arm, followed by a booster flush of 20 ml of saline solution. The study was acquired in frame mode, using a X2 zoom factor and an electrocardiographic gating. Left ventric- ular ejection fraction was calculated twice from the back- ground-subtracted time-activity curve. The diflerence between the two measurements never exceeded two ejection fracrllIn units, and the mean value was used for the data analysis.
~~t~at~ test. Ten milligrams of isosorbide dinitrate diluted
in 100 ml of isotonic saline solution was administered over 20 min. Heart rate an< blood pressure were controlled throughout the who!c test. Technetium-99m sestamibi was
injected after 15 min of infusion or earlier if there was a decrease in systolic blood pressure >2O mm
formed, as described next.
ses~amjb~ sc~~~~g~a~~y. The technetium- 99m sestamibi dose was 25 mCi (925 MBq) for both baseline and the nitrate studies, and was injected while the patient was supine. Single-photon emission computed tomographic collec- tion was performed 60 min later using an Elscint Apex %‘4 gamma camera equipped with an ultra-high resolution dli- matur with a 20% window centered at the 14O-keV photopeak of techuctium-99m. The gamma camera head rotated in step and shoot mode over a 180” arc from the 45’ right anteriO
oblique to the 45” left posterior oblique view, with 60 pro&- tions of 20 s each. hdgt3 were collected With a X1.4 ZOOm factor and stored on 64 x 64 matrices. Image reconstruction was performed using backprojection without a preprOcessi%
1284 BlSl ET AL.
NITRATE TECHNETIUM-99m SESTAMIBI IMAGING
JACC Vol. 24, No. 5 November 1, 1994:1282-9
filter and with a Wiener reconstruction filter (dumping factor 1, full-width half-maximum 8 mm). No attenuation or scatter correction was used. The transaxial slices were realigned along the heart axis.
For the quantitative evaluation of the tomographic images, the short-axis slices were used (44). Their count profiles were generated by computer software and plotted onto a two- dimensional polar map. The count profile of each study was compared with a gender-specific data base of rest technetium- 99m sestamibi studies prformed in normal control subjects. The lower limit of the normal range was set at 2.5 SD below the mean value of the gender-specific control group (44). The extent of the abnormally low uptake was first expressed as a
ent of the entire left ventricular wall. The quan r map wtls then divided into three t~rrit~~ries corr~ to the distribution of the cor~n;~~ arteries. A separate ysis was performed for each territory, and to be considered significant, a defect had to be >i2% uf the left anterior descending and left circumflex coronary artery territories and >$%I of the right coronary artery territory (45). Finally, the baseline and nitrate studies were directly ~mpare~, and the ch s in both global and individual coronary perfusion de were expressed as a percent of the extent of the defect at baseline.
Follow=~p ~~~t~o~. To determine the extent of revascu- larization, regional left ventricular function was evaluated. An asynergic vascular territory was considered to be improved when the wall motion score index decreased >22% after revascularization compared with the prerevascularizatioa value (43). The vascular territories that showed a reduction in wall motion score index after reva~ulari~atiu~ were consid- ered to be hibematitg territories that exhibited no changes were defined asfihrotic. On this basis patients were classified in two groups: group A, patients with postrevasc~larization re- gional (in at least one asynergic territory) functionai recovery; group B, patients without recovery.
Results are expr~~d a; mean value t ~~metric analysis of variance (Tuscan-Willis one-way analysis by ranks) was used for the intragroup and intergroup data er;rmperison. The comparison of proportions was made using the Fisher exact test. The relation between the changes induced by the nitrate test and the results of the re~~ulariz~tion procedures was analyzed using linear regres- sion and the Spearman rank correlation coefficient. A proba- bility value p < 0.05 was considered significant.
One patient presented with a perioperative in- farction and hence was excluded from any further data analy- sis, Data analysis includes the findings in 19 patients (Table 1). The presenting symptoms were effort angina and effort dys- pma in 13 patients, effort angina in 3 and effort dyspnea in 3. According to coronary angiography, 3 patients had one-vessel, 5 had two-vessel and 11 had three-vessel coronary artery disease. Of the 46 territories supplied by stenotic arteries, 24
Table 1. Demographic and Angiographic Date of the 19 Study Patients
R No./ Age IllfXCt Lcx RcA
Gender iyr) Site LVEF (a) @) @)
62 Ant 52 Ant + Inf 56 Ant 44 Ant 61 Amt 48 Am 50 Ant + Inf 71 Inf 59 Aa? + lnf s9 lnf 56 %nf 69 Inf 64 Inf Al Ant i- Inf 47 Iof 56 Ant 54 lllf 49 Ant 47 Inf 41 1 80 75 34 NO IOU 49 1 75 100 30 90 SO 100 29 I 0 0 23 1 7s 1 46 1 90 1 40 90 0 100 26 0 75 100 2S 90 99 90 30 9s SB 90 27 90 90 90 $8 90 7S 90 19 IiN 0 100 32 541 0 75 48 IO0 0 0 49 SO 75 IO0 34 90 SO D 35 0 90 0
Ant = anterior: F = female; Inf = inferior; LAD = left aetcrior descending eoroniiry artery; LQ = left circumflex coromary artery: LVEF = left ventricular ejeclion fraction; M = mate; pt = patient: RCA = right coronary artery.
ically identifiable collateral c~~cu~~tio~, and 6, 11 and 5 bad collateral indexes of 1, 2 and 3, respectively. 5 were the site of a previous
immediately contiguous to the infarcted ones. Nonethe of these 22 noninfarcted asynergic areas were also supplied by critically stenotic coronary arteries. The prerevascularization mean wall motion score index of the abnor
2.3 9 0.6. The prerevascularization mean left ventricular resting ejection fraction was 35.3 f: 10%.
Fo~~~w-~~ findings. Complete revascularization was ob- tained using multiple coronary artery bypass grafting in 15 patients and coronary angioplasty of all stenosed vessels in 4. The postrevascularization mean left ventricular rest ejec- tion fraction was 35.4 4 11% (p = NS vs. prerevasculariza- tion). The postrevascularizatinn mean wall motion score index of the abnormal territories was 2.2 -C 0.7 (p = NS vs. prerevascularization). Of the 45 asynergic vascular territories demonstrated before revascularization, 11 showed a reduction in wall motion score index after intervention (from 2.2 i- 0.4 to 1.5 Z!Z 0.3, p < 0.002) and were considered to have been hibernating, whereas 34 showed no changes (2.4 + 0.6 both before and after revascularization) and were classified as fibrotic. All 11 hibernating territories were found in 7 patients (at least one hibernating territory in e?ch of them) who were classified as group A, these 7 patients also showed an ejection fraction improvement. Of the 34 fibrotic vascular territories, 4 were found in the group A patients and the remaining 30 in the
JACC Vol. 24, No. 5 November 1, 1994:1X&9
.$F w 53.3 c 6.7 54.7 r- 7.9 NS
Infarct age (mo) 37.8 lr 44.3 96) i 64.1 NS
CAD (no. of diseased vessels) 2.7 -c 0.8 2.3 ? 0.8 NS Presenting ~m~toms
Effort dy;pnea and angina 6 7 NS
EtIort dyspnea 1 2 NS
Effort angina 0 3 NS
Collateral score 3 - 1.15 2 + 1.47 NS
LVEF (%) 36.8 t 10.4 34.4 2 9.9 NS
WiVISl 2.2 -c 0.3 2.4 + 0.3 NS
Data presented iWC IllCilll KIllN? i:
COrOflillgr artcry disease; LVEF = left vcn;~~cM~r ejection fraction; WMSl = wall molioa score index (mean ViIlUC for each patient).
~atie~¶ts who were classified as an ejection fraction ~mprove~~e~t.
iables of the two rent in terms of
.3 vs. 2.4 t 0.3) or collateral score On the contrary, the mean e coronary artery was greate e 11 b~bcr~at~~g than in the 34 fibrotic vascular territories (91.8 + 15.8% vs. 194.2 + 36.40/o, p < 0.05).
After revascularization, groups A and B were s~g~ifica~t~y different in terms of left ventricular global ejection fraction
NITRATE TECHNETItJM-YYm SESTAMlBl BMAGlNG 125
(group A43.4 f 9.47 0, group B 30.8 -C 8.4%, p < 0.02) as well
efect was observed in 11 hibernating areas was not significantly different from that of
nitrate infusion was performed in all patients witbo~t adverse action. Technetium-99m sestamibi was injected after 1.5 min in 15 patients; in another 4, the injection was
systolic blood pressure decreased >20 mm baseline and nitrate myocardial scintigraphi Figures 1 and 2. The results of nitrate p individual patients are shown in Table 3.
%n al% of the patients, the mean extent of ahe global efects in the nitrate technetium-99m sestamibi images was 28. 15.5% of the left ventricular wall (p = NS vs. baseline). owever a recogkablc decrease (ranging
‘Fubk 3. Results of Tec~~~et~ut~-~91~ Sestattribi Imaging
Total Extent LAD Extent LCx Extent RCA Extent
Pt No. Baseline ISDN Baseline ISDN Baseline ISDN Baseline ISDN
1 32.4 27.8 57.6 50.1 3.5 0.7 0 0 2 35.1 22.7 36.4 27.6 6.8 3.6 48.7 24.8 3 15.2 9.2 17.5 4.6 1.3 0.1 14.8 24.9 4 45 31.8 42.8 24.4 18.7 14.6 76 73.9 5 37.3 26.8 65.7 52.9 2 0 0 0 6 12.4 2.1 12.2 2.1 12.6 u 9.3 0 7 38 25.7 56.4 34.1 0 0 43.5 41.3 8 14.5 13.9 2.3 5.2 0 0.4 17 51.4 9 18 18.4 1 1 19.8 7.2 66.3 67.3 10 52.9 53.1 38.6 38.7 73.6 77.7 9s 94. I 11 38.4 41.8 25.9 27.7 64.8 63.9 35.4 53.8 I2 36.1 37 6.9 9.2 55.8 57.4 94.6 96.4 13 15.7 18.5 2.3 1.5 2.4 8.2 6X.0 12.5 14 69.1 65.6 82.8 78.5 14.4 6.7 90 91 15 27.9 30 3.6 3.4 88.6 91.1 54.7 65.4 16 11.2 13.9 22.4 25.5 0 0 II 0 17 27.1 29.4 1.2 1.5 56.5 57.5 84.4 88.4 18 43.6 44.9 79.1 78.3 06 0.5 0.2 2 19 21 20.9 0 0 88.3 88.3 34.4 33.8 - Extent is expressed in percent of the entire left ventricular wall (= total extent) and the individual coronary artery territories. ISDN = isosorbide dinitrate; other abbreviations as in Table 1.
1286 BlSl ET AL.
NITRATE TECHNETIUM-Wm SESTAMIBI IMAGING
n 1. Technetium-!&n sestamibi images from Patient 4. Up pray& polar map c&plays. Iat3 map represents myocardial count distribution under baa&e anditians, ran
studies, respectively. A clear reduction in abnormnl territories can be observed from ~NX (I) to buse, us shown in lower left imag~~s (midventricular vertical long-axis slice).
from 4% to 83%) was okserved in nine patients, seven of whom were in group A. In group A patients, the mean extent of global perfusion defect decreased (from 30.8 -C 12.2% to 20 9 2 I IQ, p = 0.06). However, in the rernai~i~~ 10 patients. ail of whom were in growp there was a slight worsening of the extent of the defect in the nitrate images. Thus, in group B in its entirety, the global extent of the uptake defect was not significantly modified in the nitrate images (32.3 5 16S% vs. baseline 31.3 -C 17.5%, p = NS). The difference in extent of perfusion changes (expressed as percent of the baseline value) induced by the nitrate test in the two groups was significant (group A, -37.4 Z 21.6% vs. group B, +5.8 -C 8.4%, p < 0.0005) (Fig. 3). The changes in global extent of the perfusion
Picks 2. Technelium-YBm sestamibi images from Patient 19. Same image disposition as in Figure 1. The lack of any change in the isoliurbide &nitrate (!SDN) study compared with abae at baseline can be readily nppreciate(l
defect induced by the nitrate test and the changes in global ejection fraction after revascularization appeared to be corre- lated (Pearson r = -0.94, SEE 7.6, p < O.OOOOOt ; Spearman rank correlation coefficient -0.9, p < 0.0001) (Fig. 4).
A significant decrease in the extent of the single-area perfusion defect after nitrate administration was observed in 14 territories; 10 territories were among the 11 hibernating. In the remaining four territories, postoperative wall motion score index remained unchanged. One territory with no reduction in extent of perfusion defect during the nitrate test had a postoperative improvement in wall motion. In the 11 hibernat- ing territories, the baseline extent of the perfusion defect decreased to 21.4 5 19.1% with nitrate imaging. In the 34 fibrotic territories, the mean extent of the uptake defect was not influenced by nitrate administration (46.6 z 33.8%). Thus, with nitrate imaging, the mean extent of the perfusion defect in the hibernating territories was significantly smaller than that in the fibrotic ones (21.4 + 19.1% vs. 46.6 -‘_ 33.8%, p < 0.05).
BBS6 ET A_.
NETIWi%YYm SESTAMlBI 6MAGlNG l28V
The study was designed to rest whcthcr the short-&c:sna
i~ern~tti~~~ myocardium. The study rationale. was twofold. irst, the favorable influence of nitrates on coronary blood QW, ~rt~cu~ar~y in the case of short-term administration, has been previously ex~~~~ited in the evaluation of asyn hypoperfused territories (3~,39,4~,4~,4~~. Second, rno imental data support the use of technetiutn-99tn sesPa
myocardium ( E-21). ood Bow. Regional blood
inistration of snb~~i~~~al or intravenous nitrates, espscially in areas of reduced coronary flow (28,30). It has been de~lollstrated (31-33) that nitro- glycerin and isosorbi e dinitrate dilate -70% of signiticant coronary slenoses. In both experi ental and human studies
-201 perfusion defect size after nitro patients with coronary occh~sion a
rnyocardial region was explained by the i ~roveme~t in coronary collateral
~~~~~~~~~ to stud
estimate of contractile reserve i ypokinetic or akinetic left ventricular regions after short-te nitrate admi~~strat~o~ was used to identify viab e ~lyocardi~m (46,47). The ~n~ct~ona~ i~~~~ove~~e~t after nitro~~yce~i~ admi~~stratioR has been re- lated to the hemodynamic effect of cardiac de&ding as weI1 as
e e~~~i~iceiK~e6~t of regional this context, collateral circulatio ccntly, nitrntc ~ld~~inistration ha
with ~~~~l~~i~fli-2~~ myocard~al scjfltj~rap~~y to improve the detection of viable myocardium (39,40). These ~re~~rn~~a~~
at nitroglycerin ad~~inistrat~o~~ before could enhance its uptake in areas with
i&y tracer. Previous ental animals (“12,14,16) have shown
of technetium-99n-6 sestamibi is m related to coronary blood flow. However, cell membrane integrity and cellular v
conditiorls fur technet
(1,3,16,18,20). Wrthe , infarcted myocardium has been
own to be unable to extract the tracer (17). In a model of reperfusion after prolonged occlusion, Sinusas et al. (19) demonstrated a significantly lower technetium-99m sestamibi uptake compared with microsphere reperfusion flow; this rcflccted the decrease in viable tissue. Similar data were reported by Freeman et al. (21).
All &SC data suggest that technetium-9Ym sestakbi could
r= - 0.94,SEE = 7.6,~ *c O.QQOOOl Spearman's=-0.90,pc0.0001
Figure 4. Correlation between the nitrate-induced change (percent of baseline value) in the total extent of perfusion and the postrevascularization change (percent of the prerevascularization value) in left ventrUdr ejection fraction (EVEF).
1288 BlSl ET AL.
NITRATE TECHNETIUM-YYm SESTAMIBI IMAGING
JACC Vol. 24. No. 5
November I, 1993:1282-O
be an excellent viability tracer. However, the results of the few available human studies were rather disappointing. ROCCO et al. (22) found that regions with a severe reduction in tracer uptake at rest may Still contain viable myocardium, as Shown by the persistence of wall motion. Using positron emission tOmO- graphic metabolic imaging, Altehoefer et al. (23) demon- strated a partially or even totally preserved glucose metabolism in half of the regions with rest technetium-99m sestamibi perfusion defects. Cuocolo et al. (24) found a significant thallium-201 uptake in regions with decreased technetium-99m sestamibi activity. Dondi et al. (25) showed that a 3-h delayed study after thallium-201 rest injection detected a higher num- ber of rcvrrsiblc defects than rest technetium-99m sestamibi
arzullo et al. (26) demonstrated that seg- rmally low ~reo~r~tive rest technctium- 99m Scstamibi uptake had u functional recovery atrer revaScu- lariiation and that the rate of false necrotic segments was
g technetium-urn sestamibi than usin
According to an increase in technetium-99m seStamibi uptake in part of the baseline hypoperfuSed territories, whereas in the majority, no nitrate- could be demonstrated. A clear relation Seems to be present between the detection of an increased tracer uptake in nitrate imaging and the recognition of functional recovery after revascularization. The patients were allocated to iwo groups according to postrcvascularization outcome. With the exception of the results of technetium-urn sestamibi imaging after isosorbide dinitrate, none of the variables cxam- ined could have distinguished between the two groups preop eratively.
Moreover, analysis of the vascular territory data sup the relation between ~st~evascularization recovery and the decrease in extent of the perfusion defect in t~chfl~tium-urn xstamibi nitrate ima$ing. The two groups of vascular tenito- ties (those with ~tr~v~~ul~ri~ation improvement ihat in- clude hi~rn~tin~ tissue and those with unch~ngcd regioct.1 function with mainly fibrotic tissue) were not signiticantly different in terms of prerevascularization wail motion Score index, collateral score index and extent of baseline technetium- 99rn Sestamibi perfusion defect. 0n the contrary, the two ups of vascular territories were differentiated preopera- cly by the response to the nitrate test. The degree of related vessel obstruction was significantly higher in the territories with postoperative improvement. This is not surprising because tt marked decrcaSe in coronary blood flow is the rule in the case Of hibernating myocardium (1,2), whereas the absence of
m wstamibi uptake in asynergic territories not r&ted to severely steenused vessels is more likely explained by the presence of fibrotic tissue (19,21).
tionS OF the study. The small patient group is the most important limitation of the study, However, this limita- iion is shared by most of the studies (22,24-27) dealing with the detection of viable hibernating myocardium using tehethm@h sestamibi. The strict SeIecLon criteria of the
patients also meant that the study cohort mainly inclu subjects with severe wall motion abnormalities an coronary artery di;r;ase. Therefore, studies in a more patient population are needed to de
technetium-99m sestamibi nitrate ima quantitative evaluation of the tomog pared the count profiles of the baseli those of a data base of formal
tracer uptake were consi
diwm. Therefore, it is not possible to define the relative reliability of tcc~netiu~~l-99m sesta
sitron emission tomo~rapby or thal
Further studies are wa~anted to define the value of technetium- 99m sestamibi nitrate imaging and its role in the management of patients with chronic coronas artery disease and left ventricular dySfunction.
WC tbank Raffacle Giubbini, MD, and Owio Zoccarato, MS, of the Nuclear Medicine L&oratory of the Brtxia Civic Hospital, Brescia. Italy, for providing the data base of normal control subjects.
ees
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