- Email: [email protected]
Preoperative identification of viable myocardium: Effectiveness of nitroglycerine-induced changes in myocardial Sestamibi uptake
ELSEWER SCIENCE’
-.--_-“--
rative identification of viable myocasdlum: veness of nitroglycerine-induced chatn myocardial Sestamibi uptake C. Greco’, M. Ciavolellats, G. TanziW, R. Sinatra+, F. Mauinat, 0. Schillaci’, R. TavolaroS, F. Scopinaro’, P.P. Campa+ and B. Marina+ ‘Institute Medicine,
of cardiac University
Surgery and ‘Section of NUCleaF Medicine, “La Sapienza”, Rome, b/y
DepartmerIt
of EXpeFimenW
In order to predict tissue viability in infarcted myocardial areas, changes induced by nitroglycerine infusion on Sestamibi myocardial uptake were evaluated in 37 patients with previously confirmed myocardial infarction undergoing coronary artery bypass grafting, and compared with echocardiographic and perfusional changes occurring after the operation. The improvement of Sestamibi uptake after nitroglycerine correctly classified 24/26 (92%) patients showing postoperative improvement of wall motion in the infarcted area, whereas 24/31 (77%) patients with nitroglycerine-induced increase in Sestamibi uptake had improved wall motion after operation. The presence of collateral flow to the infarcted area was associated with a significantly (P < 0.01) higher increase in Sestamibi uptake both during nitroglycerine infusion and postoperatively. An increase in wall motion score after operation was associated with a significantly higher (P < 0.05) increase in Sestamibi uptake score during nitroglycerine infusion. Thus, the results of this study suggest that Sestamibi perfusional myocardial scintigraphy during nitroglycerine infusion is capable of assessingviable but chronically hypoperfused myocardium and predicting postoperative wall motion and perfusional improvement, to yield the best results in patients with evidence of collateral circulation that supplies the infarcted area. 0 1998 The International Society of Cardiovascular Surgery. Published by Elsetier Science Ltd. All rights reserved Keywords: myocardial infarction, nitroglycerine, perfusion, revascularization, viability
The concept of hibernating myocardium has enlarged the indication for revascularizing dysfunctioning left ventricles, thus giving a new chance to patients who were previously classified as affected by irreversible ischemic cardiomyopathy [ 11. As a corollary, the identification of hibernating myocardium is important in predicting the functional outcome of such patients after revascularization[2]. Among the many methodological approaches proposed to assess the effectiveness of revascularizing infarcted myocardial areas, in an attempt to predict
Correspondence to: Dr C. Greco, Istituto ersita ‘La Sapienza’, Viale de1 Policlinico,
CARDIOVASCULAR
SURGERY
APRIL
di Cardiochirurgia, Univ00166-Roma, Italia
1996 VOL 6 NO 2
myocardial viability, radionuclide techniques are currently widely used[3-61. Sestamibi (MIBI) scintigraphy already represents an alternative to ‘O’T1[7, 81, in order to detect myocardial ischemia, and evidence has also been provided that MIBI myocardial uptake is dependent on both blood flow and metabolic balance[o-1 11. Nitrates are known to increase blood supply to the myocardium by exerting direct local metabolic effects and to dilate both collateral circulation and coronary arteries presenting with eccentric stenoses [ 12-l 41. Such behaviour enhances the dehvet-y of a perfusional tracer to the tissue, and allows myocardial cells to take-up and concentrate it to a greater extent than in basal conditions, if energydepending mechanisms are still available, i.e. only if the cell is still viable]1 5, 161. 149
NTG-induced
perfusional
changes
predict
viability;
C. Greco
et al.
The aim of the study was to evaluate the changes induced by nitroglycerine (NTG) i.v. administration on MIBI uptake by infarcted myocardial areas, and to compare these findings with wall motion and perfusional changes obtained after revascularization, in order to predict tissue viability.
Methods Patients Among patients undergoing heart catheterization at our institution, in order to evaluate the feasibility of myocardial revascularization procedures, 37 consecutive male patients (mean age s.d.: 58.9 + 7.5 years) were selected for the study, because of the detection at left ventricular (LV) angiography of a poorly contracting myocardial area supplied by a stenotic main coronary artery. A history of previous ( > 6 months old) myocardial infarction was present in all patients, and was confirmed by the presence of pathological Q waves at ECG. Written informed consent was obtained from each patient. Table 1 shows the characteristics of the patients. All patients underwent three radionuclide studies, two preoperatively, at rest (MIBI-1) and during NTG infusion 48 h later (MIBI-NTG), and a third one at rest > 3 months after surgery (MIBI-2). A standard echocardiographic study was carried out < 14 days before the operation (ECHO-l) and at > 3 months after (ECHO-2).
Table 1
Summary
of clinical and instrumental
Patients (n) Mean age (years) l/2/3-vessel disease (n) Stenoses: < 90% Stenoses 9C-99% Stenoses 100% Collaterals (O/1/2/3) ECHO-l score ECHO-Z score ECHO improvement (n) MIBI-1 score MIBI-NTG score MIBI improvement (n) MIBI-2 score MIBI-2 improvement (n)
data and of study results 37 58.9 k 7.5 5/21/l 1 9 (24%) 7 (19%) 21 (57%) 16/6/l II4 7.81 f 4.50 10.73 f 4.97 26 (70%) 5.1‘9 + 3.10 7.16 f 3.18 32 (86%) 7.81 f 2.47 31 (86%)
ECHO-l, preoperative echocardiographic study: ECHO-Z. postoperative echocardiographic study: ECHO improvement, patients showing improved regional wall- motion’ postoperatively: MIBI-1, preoperative basal radionuc!ide study; MIBI-NTG. preoperative radionuclide study during nitroglycerine infusion: MIBI improvement, patients showing regional perfusional improvement after nitroglycerine infusion; MIBI-2, postoperative basal radionuclide study; MIBI-2 improvement, patients showing regional perfusional improvement postoperatively, in comparison with basal preoperative study. MIBI-2 was carried out in 36 patients, as one patient died before undergoing postoperative study.
IS0
Heart
catheterization
Patients underwent biplane LV angiography and selective coronary angiography in standard orthogonal views. Coronary stenoses ( 1 70%) were visually evaluated by two investigators, and disagreements were resolved by a third physician. Coronary collateral circulation was visually graded from 0 to 3 (0 = no visible filling, 1 = filling of side branches only, 2 = partial filling of epicardial segments, 3 = complete filling of epicardial segments) [ 171. Echocardiographic
study
All studies were recorded in the standard parasternal long and short-axis, and apical 2- and 4-chamber view, and subsequently interpreted by two experienced investigators who were unaware of the pathological results of heart catheterization, as well as of MIBI results. LV was divided into 16 segments according to the criteria recommended by the American Society of Echocardiography[l8]. LV wall motion abnormalities were identified by comparing segment motion with that of the adjacent ones. Each segment was graded as normal (2), hypokinetic (l), akinetic or dyskinetic (0), and a wall motion score was determined for infarcted areas by adding up the scores of the related segments. The comparison of scores obtained at ECHO-l and ECHO-2 allowed detection of wall motion improvement. Scintigraphic
study
The tracer was prepared and labelled according to the manufacturer’s guidelines (Cardiolite, DuPont de Nemours). Scans were acquired at least 60 min after administration of a bolus of 740 MBq of 99 mTc-MIBI in 0.5 ml, in order to increase heart/background activity ratio. A gamma camera (Starcam 2000, General Electric) equipped with a high sensitivity parallel hole collimator was used. Three planar scans in 128 x 128 matrix were acquired in anterior, 45” and 70” left anterior oblique views, achieving at least 1,OOO,OOO counts/scan, and processed by interpolative background subtraction. A quantitative processing was performed after orthogonal to polar co-ordinate conversion, through the comparison to reference profiles obtained from a pool of normal scans at our laboratory. Average normal reference profiles were thus obtained, with a mean standard deviation (s.d.) of 25% (range: 22-29%). Each view was divided into five sectors[8]. Sectors were graded on the basis of quantitative profiles as follows: > 75% of maximal uptake (grade 3); 5 l-75 % of maximal uptake (grade 2); 26-50% of maximal uptake (grade 1); < 26% of maximal uptake (grade 0). An uptake score was then determined for infarcted areas by adding up the scores of the related sectors. CARDIOVASCULAR
SURGERY
APRIL
1998 VOL 6 NO 2
NTG-induced perfusional changes predict viabiktv: I:. i;rero et RI
NTG
test
Nitrates and calcium-channel blockers were discontinued 2 days before the study, digoxin and betablockers 5 days before. The pharmacological test was performed in the morning gfter overnight fasting. ECG was monitored in leads DII, V2 and V5 throughout the test, and blood pressure was recorded befure and every minute after starting NTG infusion. NTG was administered into an antecubital vein, by mesns of a microprocessor-controlled pump, at a rate of I pg/kg per min, and increased to 1.5 per min after the*t 3min of infusion. MIBI was injected into a controlateral vein when a decrease of 1 10 mmHg in systolic blood pressure was reached. NTG administration was continued at a rate of 0.5 pg/kg per min over 2 min after MIBI injection. There were no complications related to the test. Statistical
a3a&ysis
Continuous variables are expressed as mean values + 1 s.d. Student’s t-test for paired data was used to compare both wall motion and perfUsiona score changes. Statistical significance was accepted as P < 0.05.
Results Catheterizaalm
test
Blood pressure decreased on average from 135.6 + 14.1/80.5 -t 6.4mmHg to 114.7 + 11.7/73.6 + 4.3 mmHg (P < O.OOOl), whereas heart rate increased from 71 * 9 bpm to 82 f 7 bpm (P < 0.000 1). Average duration of NTG infusion was 4.15 + 0.97 min. Eleven patients complained of mild to moderate headache during NTG administration, CARDIOVASCULAR
SURGERY
Surgfeai
and pimegm&w
d data
In all patients complete myacar&l revascuiarization was attempted, for an average of 3.7 gratis per patient. Internal mammary 4~ was us&d to revas-
rem&& patients r-tied improvemenr tional capacity after surgery. Echocardiographic
of func-
data
At ECHO- 1, average LV end-diastolic and end-systolic diameters and f&&on@ shiorten~g were 56.5 f 7.1 mm, 44.1 f 6.5 mm a& 21 .Q rt 4,7%, respectively. At ECHO-2 they wepe 52.3 i: 5.3 mm (P <. O.OOOl), 37.2 f 4.9 mm (P < O.@W) and 24.1 + 4.9% (P < O.OO;O-I>, respegtivety. Average infarctrelated territory score was 7.81 f 4.50 at ECHO-l, and 10.73 & 4.97 at ECHO-2 (P < O&01>, because of an increase of + 2.93 & 3.21 detected in 26 patients (70%). Rad.i+mmAide data
data
Average LV ejection fraction was 4 1% (range = 3552%). Anterior infarction was detected in 27 patients, whereas the remainder presented with inferior infarction. Infarct-related arteries presented with stenoses graded as < 90%, 90-99% and 100% in 9, 7 and 21 cases, respectively. Significant coronary stenoses were found on left anterior descending artery (LBD) in 35 patients, on left circumflex artery territory in 21 patients, and on right coronary artery (RCA) territory in 26 patients. Thus, 11 patients presented with 3-vessel disease, 21 with 2-vessel disease, and five w&h l-vessel disease, respectively. Collaterals to LAD were detected in 14 patients, and were graded as 1, 2 and 3 in 4, 8 and 2 cases, respectively. Collaterals to RCA were found in seven patients, and were gmded as 1, 2 and 3 in two, three and two cases, respectively (Table I). NTG
but in no case did NTG infusion have to be stopped because of side-effects. AH parameters recovered to basal values within 10 min from the end of NTG infusion.
APRIL
1998 VOL 6 NO 2
Average MIBI uptake score was 5.19 f 3.10 at MIBI-1, and 7.16 + 3.18 at MIBI-NTG, for an average increase of + 1.97 + 1.59 (P c’ 0.001) detected in 32 patients (86%) (Figure 1). MIBI-2 average score in the 36 patients studied was 7,81 + 2.47, for an average increase of + 2.62 f 1.80 (P < 0.001) detected in 31 patients (86%), in comparison with MIBI-1. NT&induced increase in MI&I up&e (Table 2) was significantly higher in rhe Ifs patients with collaterals score > 1 in comparia6#rs wi& patients with score 5 1 ( + 3.0 f 1.69 nm + 1.27 I 1.08, P < O.Ol), whereas wail motion dH+mces were not statistically signif&mt ( + 3.06 f 2.55 U~YSUS+ 2.64 rt 3.62, P = N.S.). A~~, out of five patients who did not improve Itpl;EBI upmke after NTG, four showed no collat&&~ and one had a significant stenosis on the vessel supplying collateral circulation. A positive change in LV wall motion after the operation (Table 3) was associated with a significantly higher change in MIBI uptake after NTG infusion ( + 2.31 + 1.64 verssus-t 1.10 i 1.20, P < 0.05). Also the change in MIBI uptake after operation was significantly higher in patients showing an increase in LV wall motion ( + 3.27 ? I .5 I ‘ZWSZLS + 0.60 + 0.70, I’ cc 0.001). IS1
NTG-induced
perfusional
changes
predict
viability:
C. Greco
et al.
MIBI-2
MIBI-NTG
MIBI-I
ANTERIOR
VIEW
LAO 45O VIEW
LAO 70° Figure 1 From left to right, preoperative basal (MIBI-1). preoperative 45” left anterior oblique (middle) and 70” left anterior oblique (bottom) and basal anteroseptal walls at MIBI-NTG scan is visible. Postoperative
VIEW
nitroglycerine (MIBI-NTG) and postoperative basal (MIBI-2) scans in anterior (top), views are shown. A clear-cut increase of tracer uptake on the anterior, anterolateral scans show increased tracer uptake in the same myocardial zones
CARDlOVA8CULAR
SURGERY
APRIL
1998
VOL 6 NO 2
NTG-induced Table 2 Different distribution of collateral circulation Collateral
circulation
NTG-induced
perfusional
yes (n = 32) 15 1’7
yes (n = 15) no (n = 22) NTG. nitroglycerine:
Table 3
of perfusional
done patient
Wall motion
improvernent
improvement
undergoing
perfusionai
NTG. nitroglycerine:
%ne patient
died before
wall motion
postoperative
radionuclide
infusion
and by revascularization
improvement
postoperative
improvement
predict
and revascularization.
viabi/i$ dependirig
Postoperative
perfusionai
I:. Greco
et al.
on the presence
imorovement” ---____
“b :,: : 5: ? 3 -...----II___
yes (n = 31) 13 18
in predicting
Postoperative yes (n = 311 24 ‘7 radionuclide
changes
study.
no (n = 5) 2 3 undergoing
Infusion
no (n = 11) 5 6
yes (n = 26) 10 16
changes induced by nitroglycerine
NTG-induced
by nitroglycerine
Postoperative
yes (n = 32) 24 8
yes in = 26) no (n = 11)
changes induced
no (n = 5) 0 5
died before
Accuracy of tracer uptake
and functional
perfusional
postoperative
perfusional
wall motion improvement _.-~_____
improvement’ no (V I: 2 3
rj
study.
The improvement of MIBI uptake after NTG infusion was correctly classified as viable in 24126 (92%) infarcted territories of patients showing wall motion improvement after operation, whereas 24/3 1 (77%) patients showing NTG-induced increase in MIBI uptake presented wall motion improvement postoperatively.
inhibition of oxidative phosphorylation reduces its uptake, and in the presence of severe post-ischaemic injury, both mitochondrial and plasma membrane depolarize, thereby decreasing rhe driving force for MIBI retention.
Discussion
Several tests have been coupled to radionuclide methods in an attempt to induce some changes compatible with myocardial viability, ranging from low dose dobutamine infusion[2 11, to a isometric stress test[22], or to NTG administration[23]. The latter acts through a direct effect on the coronary wall, as well as through systemic haemodynamic and metabolic effects, which have been widely documented in patients with coronary artery disease. In fact, nitrates are known to improve oxygen delivery to ischaemic areas by increasing total myocardial blood flow through stenotic coronary arteries and collateral circulation[24, 251. This is the result of the recruitment of a pre-existing collateral network, which is often abundant in myocardial zones supplied by occluded or nearly occluded vessels, as well as of the dilation of narrowed vessels at the level of epicardial eccentric stenoses and/or of muscular pre-arterioles. Additionally, the effects on preload and afterload induce a decrease in LV volume and wall tension, resulting in a reduction in myocardial oxygen requirements [ 121. The increase in blood supply provided by NIG i.v. infusion allows an increased MIBI delivery to akinetic areas, which can retent and concentrate it, as mentioned above, only if basal energy-depending mechanisms are still available, i.e. only if the cell is still viable.
It would be of major clinical interest to find a simple and repeatable method capable of predicting recovery of function in territories presenting with an abnormal wall motion, more likely to reflect irreversible dysfunction and scar. Many methodological approaches have been proposed and are currently tested, such as dobutamine echocardiography, fatty acid, 201T1 and MIBI scintigraphy, and positron emission tomography[2-6, 191. Tracer
characteristics
MIBI is a lipophilic cationic compound with high whose myocardial uptake myocardial affinity, depends on both blood flow and metabolic balance[9-111. In fact, MIBI capture is proportional to blood flow under a wide range of flows, but its retention depends on passive diffusion across both cellular and mitochondrial inner membranes in response to large negative transmembrane potentials. Thus, mitochondrial localization and further concentration of the tracer are favoured by intermediary metabolism of substrates delivering reducing equivalents to mitochondrial electron transfer cytocromes [9]. Experimental studies[20] showed MIBI accumulation to be dependent upon metabolic status, as the CARDIOVASCULAR
SURGERY
APRIL
1998
VOL 6 NO 2
Action
of nitrates
153
NTG-induced
Study
perfusional
changes
predict
viability:
C.
GreCO
et al.
results
Differently from previous investigators [26], who administered NTG orally, we preferred to use i.v. infusion, in order to obtain fast and short-lasting (< 10 min in our study) haemodynamic systemic and local effects. In this way we attempted to acquire basal and NTG perfusional scans in the same haemodynamic conditions, thus avoiding long-lasting improvements in left ventricular wall motion from oral NTG administration, which is eventually responsible for a partial volume effect[27]. The increased MIBI uptake detected in this study after NTG administration in infarcted segments suggests the capability of this method to identify viable but chronically hypoperfused myocardium. The presence of collateral circulation with high-degree retrograde filling allowed the best improvement of myocardial MIBI uptake to be obtained. These findings were confirmed by repeating radionuclide study after revascularization. The majority of areas supplied by collaterals and showing increased MIBI uptake after NTG infusion, presented with an improvement in LV wall motion at echocardiography after revascularization. Thus, possibly collateral vessels may be highly effective in maintaining a minimal myocardial perfusion and tissue viability, but may not be effective enough to preserve wall motion (hibernating myocardium). Prediction. of improvement in postoperative MIBI uptake was very accurate by using NTG infusion, possibly because NTG could determine a better distribution of tracer, oxygen and substrates to still viable cells, thus increasing myocardial uptake. Experimental studies[lO, 16, 26, 271 have suggested that cell viability is necessary for myocardial MIBI uptake and retention in the presence of adequate blood flow. Further evidence of that is provided by the close relation shown by MIBI-NTG and MIBI2 uptake changes in comparison with MIBI-1. Study
limitations
A limitation of the study is represented by the selection bias of such a small study group. Certainly the accuracy and clinical effectiveness of the method needs to be tested on larger patient groups, in order to draw pathophysiological and prognostic implications. Additionally, the simultaneous assessment of several variables, such as LV performance together with myocardial perfusion, or echocardiographic study during NTG administration, would possibly have clarified the behaviour of infarcted areas, as well as NTG infusion during coronary angiography, in order to discriminate the different contributions to the improvement in blood flow due to collaterals and to dilation of eccentrically narrowed coronary vessels. The same applies to a postoperative coronary
154
arteriographic study, which if performed, would have strengthened the conclusions of the study, confirming radionuclide perfusional results. MIBI scintigraphy during NTG infusion proved to be a useful, feasible and safe tool for the detection of viable myocardium in areas with abnormal kinesis, thus predicting wall motion and perfusion improvement after revascularization. At present, collaterals seem to represent the major independent variable related to viability, though future studies are necessary to rule out other anatomic and clinical parameters possibly conditioning it, such as the position, the degree as well as the morphology of coronary stenoses.
References 1. Rahimtoola, S., The hibernating myocardium. Anierican Heart journal, 1989, 117, 211-221. 2. Tillisch, J. H., Bnmken, R., Marshall, R. et al., Reversibility of cardiac wall motion abnormalities predicted by positron tomography. New England Journal of Medicine, 1986, 314, 884.-888. 3. Murray, G., Schad, N., Ladd, W. er al., Metabolic cardiac imaging in severe coronary disease: Assessment of viability with iodine-123-iodophenylpentadecanoic acid and multicrystal gamma camera, and correlation with biopsy. Journal of Nuclear Medicine, 1992, 33, 1269-1277. 4. Marzullo, I’., Parodi, O., Reisenhofer, B. et aZ., Value of rest thallium-201/technetium-99m Sestamibi scans and dobutamine echocardiography for detecting myocardial viability. America?r ~oumal of Cardiology, 1993, 71, 166-172. V. and Bonow, R. O., Current diagnostic technique of 5. Dilsizian, assessing myocardial viability in patients with hibernating and stunned myocardium. Circulation, 1993, 87, l-20. 6. Sawada, S., Allman, K., Muzik, 0. et al., Positron emission tomography detects evidence of viability in rest technetium-99m Sestamibi defects. Journal ojthe American College of Cardiology, 1994, 23, 92-98. 7. Ciavolella, IM., Tomai, F., Vicchio, D. et al., Single-day combined evaluation of regional myocardial perfusion and function at rest and neak exercise with 99mTcMIBI in natients with coronary artery disease. International Journal of Cardiac Imaging, 1993,9,99 111. J., Roy, L. T. et al., Comparison of tech8. Kiat, H., Maddahi, netium 99m methoxy isobutyl isonitrile and thallium 201 for evaluation of coronary artery disease by planar and tomographic methods. Anzerica?z Heart Journal, 1989, 117, l-l 1. 9. Freeman, I., Grunwald, A. M., Hoory, S. and Bodenheimer, M. M., Effect of coronary occlusion and myocardial viability on myocardial activity of technetium-99m-isonitrile. Journal of Nuclear Medicine, 1991, 32, 292-298. 10. Piwnica-Worms, D., Kronauge, J. F. and Chiu, M. L., Uptake and retention of hexakis (2-methoxyisobutyl isonitrile) Technetium(I) in cultured chick myocardial cells Mitochondrial and plasma membrane potential dependence.. Circulation, 1990, 82, 1826-1838. R. C., Silber, S. and Pohost, G. M., Relations of the 11. Canby, myocardial imaging agents 99mTc-MIBI and 201Tl to myocardial blood flow in a canine model of myocardial ischemic insult. Circulation, 1990, 81, 289-296. 12. Abrams, J., Mechanisms of action of the organic nitrates in the treatment of myocardial ischemia. American 3uurnal oj(2ardioloB, 1992, 70, 30B-4r2B. 13. Brown, B. G., Bolson, E. L., Peterson, R. B. et al., The mechanism of nitroglycerin action. Stenosis vasodilation as a major component of drug response. Circulation, 198 1, 65, 1089-l 097. 14. Jugdutt, B. J., Becker, L. C., Utchings, G. M. et al., Effect of
CARDIOVASCULAR
SURGERY
APRIL
1998 VOL 6 NO 2
NTG-induced
15
16
17
18
19
20
21
intravenous nitroglycerin on collateral blood flow and infarct size in the conscious dog. Circulation, 1981, 63, 17--28. Beanlands, R. S., Dawood, I;., Wen, W. et aZ., Are the kinetics of technetium-99m methoxyisobutyl isonitrile affected by cell metabolism and viability? Circulation, 1990, 82, 1802-1814. Crane, I’., Ialiberte, R., Heminway, S. ez al., Effect of mitochondnal viability and metabolism on technetium-99m-Sestamibi myocardial retention. Europem Journal of Nuclear Medicine, 1993, 20, X-25. Cohen, M. V. and Rentrop, K. P., Limitation of myocardial rschemia by collateral circulation during sudden controlled coronaty artery occlusion in human subjects: a prospective study. Circulutiou, 1986, 74, 469. 476. Schiller, !q. B., Shah, P. M., Crawford, M. ez ol., Recommendations for quantitation of 2-D echocardiography. 3oumal of the .~lnwicmz Socieq o.f Echocardiography, 1989, 2, 358-367. Barilla, F., Gheorgbiade, LU., Alam, H. et al., Low-dose dobutamine in patients with acute myocardial infarction identifies viable but not contractile myocardium and predicts the magnitude of improvement in wall motion abnormalities in response to coronary revascularization. Anzeti~7r Heart Journal, 1991, 122, 1522 1531. (:arvalho, I’. A., Chiu, M. I,., Kronauge, J. F. et al., Subcellular distribution and analysis of technetium-99m-MIBI in isolated perfused rat hearts. ,$unzui of ~Yuclear Medicine, 1992, 33, 1516 1521. Barilli, F., De Vincentis, G., Gemelli, F. et al., (1994)(abstr.) Functional recovery of viable myocardium with dobutamine
CARDIOVASCULAR
SURGERY
APRIL
1998 VOL 6 NO 2
22.
23.
24.
25.
26.
27.
perfusronal
changes
predict
viabi\iti/:
i: C%w
ez- a/.
stress echocardiography and 99mTcSesramibi upmk?. f~uropmr Heart Journal, 15, 435. Quinones, M. A., Gaasch, W. H., Watsser, E. ,.f ,z/., An analysis of the left ventricular response to isometric ~~xrrcisr .#~renc~r~ Hean 30urn4 1974, 88, 29--36. Tanzilli, G., Greco, C., Scopinaro, F. 2t ul., Enhanced detccticln of viable myocardium by 99mTc-MIBI imaging after nitratemediated vasodilation. Journal qf I\‘uc!em Htr&q~ md .Medicine. 1992, 136, 163-164. Winbury, IM. M., Redistribution of left ventricular blood flow produced by nitroglycerin. Circulation Ke.search, 197 1, B(Suppl. I), 140-147. Fujita, M., Yamanishi, K., Hirai, T. L’I cri., Significance of collateral circulation in reversible left ventricular asinergy bv nitroglycerin in patients with relatively recent myocardial innuction. American Heart Journal, 1990, 120, 521 538. Galli, M., &Marcassa, C., Imparato, A. ~‘r Gi.> Effxrs of nitroglycerin by Technetium-99m Sestamibi tomtlscmtigraphy on resting global myocardial hypoperfusion in stable patients with healed myocardial infarction. Rmericcz?l ,@~i& lli t :/&io~o~~, 1994, 74, 843-848. Sinusas, A. J., Shi, Q,, Vitols, P. J. t?z oi., Impact ot regional ventricular function, geometry, and dobutaminr stress on quantitative 99mTc-Sestamibi defect size. Cir&,&~~i. ! 0173. 8X. 2224 2234.
Paper
accepted
lo October
1997
15s
-.--_-“--
rative identification of viable myocasdlum: veness of nitroglycerine-induced chatn myocardial Sestamibi uptake C. Greco’, M. Ciavolellats, G. TanziW, R. Sinatra+, F. Mauinat, 0. Schillaci’, R. TavolaroS, F. Scopinaro’, P.P. Campa+ and B. Marina+ ‘Institute Medicine,
of cardiac University
Surgery and ‘Section of NUCleaF Medicine, “La Sapienza”, Rome, b/y
DepartmerIt
of EXpeFimenW
In order to predict tissue viability in infarcted myocardial areas, changes induced by nitroglycerine infusion on Sestamibi myocardial uptake were evaluated in 37 patients with previously confirmed myocardial infarction undergoing coronary artery bypass grafting, and compared with echocardiographic and perfusional changes occurring after the operation. The improvement of Sestamibi uptake after nitroglycerine correctly classified 24/26 (92%) patients showing postoperative improvement of wall motion in the infarcted area, whereas 24/31 (77%) patients with nitroglycerine-induced increase in Sestamibi uptake had improved wall motion after operation. The presence of collateral flow to the infarcted area was associated with a significantly (P < 0.01) higher increase in Sestamibi uptake both during nitroglycerine infusion and postoperatively. An increase in wall motion score after operation was associated with a significantly higher (P < 0.05) increase in Sestamibi uptake score during nitroglycerine infusion. Thus, the results of this study suggest that Sestamibi perfusional myocardial scintigraphy during nitroglycerine infusion is capable of assessingviable but chronically hypoperfused myocardium and predicting postoperative wall motion and perfusional improvement, to yield the best results in patients with evidence of collateral circulation that supplies the infarcted area. 0 1998 The International Society of Cardiovascular Surgery. Published by Elsetier Science Ltd. All rights reserved Keywords: myocardial infarction, nitroglycerine, perfusion, revascularization, viability
The concept of hibernating myocardium has enlarged the indication for revascularizing dysfunctioning left ventricles, thus giving a new chance to patients who were previously classified as affected by irreversible ischemic cardiomyopathy [ 11. As a corollary, the identification of hibernating myocardium is important in predicting the functional outcome of such patients after revascularization[2]. Among the many methodological approaches proposed to assess the effectiveness of revascularizing infarcted myocardial areas, in an attempt to predict
Correspondence to: Dr C. Greco, Istituto ersita ‘La Sapienza’, Viale de1 Policlinico,
CARDIOVASCULAR
SURGERY
APRIL
di Cardiochirurgia, Univ00166-Roma, Italia
1996 VOL 6 NO 2
myocardial viability, radionuclide techniques are currently widely used[3-61. Sestamibi (MIBI) scintigraphy already represents an alternative to ‘O’T1[7, 81, in order to detect myocardial ischemia, and evidence has also been provided that MIBI myocardial uptake is dependent on both blood flow and metabolic balance[o-1 11. Nitrates are known to increase blood supply to the myocardium by exerting direct local metabolic effects and to dilate both collateral circulation and coronary arteries presenting with eccentric stenoses [ 12-l 41. Such behaviour enhances the dehvet-y of a perfusional tracer to the tissue, and allows myocardial cells to take-up and concentrate it to a greater extent than in basal conditions, if energydepending mechanisms are still available, i.e. only if the cell is still viable]1 5, 161. 149
NTG-induced
perfusional
changes
predict
viability;
C. Greco
et al.
The aim of the study was to evaluate the changes induced by nitroglycerine (NTG) i.v. administration on MIBI uptake by infarcted myocardial areas, and to compare these findings with wall motion and perfusional changes obtained after revascularization, in order to predict tissue viability.
Methods Patients Among patients undergoing heart catheterization at our institution, in order to evaluate the feasibility of myocardial revascularization procedures, 37 consecutive male patients (mean age s.d.: 58.9 + 7.5 years) were selected for the study, because of the detection at left ventricular (LV) angiography of a poorly contracting myocardial area supplied by a stenotic main coronary artery. A history of previous ( > 6 months old) myocardial infarction was present in all patients, and was confirmed by the presence of pathological Q waves at ECG. Written informed consent was obtained from each patient. Table 1 shows the characteristics of the patients. All patients underwent three radionuclide studies, two preoperatively, at rest (MIBI-1) and during NTG infusion 48 h later (MIBI-NTG), and a third one at rest > 3 months after surgery (MIBI-2). A standard echocardiographic study was carried out < 14 days before the operation (ECHO-l) and at > 3 months after (ECHO-2).
Table 1
Summary
of clinical and instrumental
Patients (n) Mean age (years) l/2/3-vessel disease (n) Stenoses: < 90% Stenoses 9C-99% Stenoses 100% Collaterals (O/1/2/3) ECHO-l score ECHO-Z score ECHO improvement (n) MIBI-1 score MIBI-NTG score MIBI improvement (n) MIBI-2 score MIBI-2 improvement (n)
data and of study results 37 58.9 k 7.5 5/21/l 1 9 (24%) 7 (19%) 21 (57%) 16/6/l II4 7.81 f 4.50 10.73 f 4.97 26 (70%) 5.1‘9 + 3.10 7.16 f 3.18 32 (86%) 7.81 f 2.47 31 (86%)
ECHO-l, preoperative echocardiographic study: ECHO-Z. postoperative echocardiographic study: ECHO improvement, patients showing improved regional wall- motion’ postoperatively: MIBI-1, preoperative basal radionuc!ide study; MIBI-NTG. preoperative radionuclide study during nitroglycerine infusion: MIBI improvement, patients showing regional perfusional improvement after nitroglycerine infusion; MIBI-2, postoperative basal radionuclide study; MIBI-2 improvement, patients showing regional perfusional improvement postoperatively, in comparison with basal preoperative study. MIBI-2 was carried out in 36 patients, as one patient died before undergoing postoperative study.
IS0
Heart
catheterization
Patients underwent biplane LV angiography and selective coronary angiography in standard orthogonal views. Coronary stenoses ( 1 70%) were visually evaluated by two investigators, and disagreements were resolved by a third physician. Coronary collateral circulation was visually graded from 0 to 3 (0 = no visible filling, 1 = filling of side branches only, 2 = partial filling of epicardial segments, 3 = complete filling of epicardial segments) [ 171. Echocardiographic
study
All studies were recorded in the standard parasternal long and short-axis, and apical 2- and 4-chamber view, and subsequently interpreted by two experienced investigators who were unaware of the pathological results of heart catheterization, as well as of MIBI results. LV was divided into 16 segments according to the criteria recommended by the American Society of Echocardiography[l8]. LV wall motion abnormalities were identified by comparing segment motion with that of the adjacent ones. Each segment was graded as normal (2), hypokinetic (l), akinetic or dyskinetic (0), and a wall motion score was determined for infarcted areas by adding up the scores of the related segments. The comparison of scores obtained at ECHO-l and ECHO-2 allowed detection of wall motion improvement. Scintigraphic
study
The tracer was prepared and labelled according to the manufacturer’s guidelines (Cardiolite, DuPont de Nemours). Scans were acquired at least 60 min after administration of a bolus of 740 MBq of 99 mTc-MIBI in 0.5 ml, in order to increase heart/background activity ratio. A gamma camera (Starcam 2000, General Electric) equipped with a high sensitivity parallel hole collimator was used. Three planar scans in 128 x 128 matrix were acquired in anterior, 45” and 70” left anterior oblique views, achieving at least 1,OOO,OOO counts/scan, and processed by interpolative background subtraction. A quantitative processing was performed after orthogonal to polar co-ordinate conversion, through the comparison to reference profiles obtained from a pool of normal scans at our laboratory. Average normal reference profiles were thus obtained, with a mean standard deviation (s.d.) of 25% (range: 22-29%). Each view was divided into five sectors[8]. Sectors were graded on the basis of quantitative profiles as follows: > 75% of maximal uptake (grade 3); 5 l-75 % of maximal uptake (grade 2); 26-50% of maximal uptake (grade 1); < 26% of maximal uptake (grade 0). An uptake score was then determined for infarcted areas by adding up the scores of the related sectors. CARDIOVASCULAR
SURGERY
APRIL
1998 VOL 6 NO 2
NTG-induced perfusional changes predict viabiktv: I:. i;rero et RI
NTG
test
Nitrates and calcium-channel blockers were discontinued 2 days before the study, digoxin and betablockers 5 days before. The pharmacological test was performed in the morning gfter overnight fasting. ECG was monitored in leads DII, V2 and V5 throughout the test, and blood pressure was recorded befure and every minute after starting NTG infusion. NTG was administered into an antecubital vein, by mesns of a microprocessor-controlled pump, at a rate of I pg/kg per min, and increased to 1.5 per min after the*t 3min of infusion. MIBI was injected into a controlateral vein when a decrease of 1 10 mmHg in systolic blood pressure was reached. NTG administration was continued at a rate of 0.5 pg/kg per min over 2 min after MIBI injection. There were no complications related to the test. Statistical
a3a&ysis
Continuous variables are expressed as mean values + 1 s.d. Student’s t-test for paired data was used to compare both wall motion and perfUsiona score changes. Statistical significance was accepted as P < 0.05.
Results Catheterizaalm
test
Blood pressure decreased on average from 135.6 + 14.1/80.5 -t 6.4mmHg to 114.7 + 11.7/73.6 + 4.3 mmHg (P < O.OOOl), whereas heart rate increased from 71 * 9 bpm to 82 f 7 bpm (P < 0.000 1). Average duration of NTG infusion was 4.15 + 0.97 min. Eleven patients complained of mild to moderate headache during NTG administration, CARDIOVASCULAR
SURGERY
Surgfeai
and pimegm&w
d data
In all patients complete myacar&l revascuiarization was attempted, for an average of 3.7 gratis per patient. Internal mammary 4~ was us&d to revas-
rem&& patients r-tied improvemenr tional capacity after surgery. Echocardiographic
of func-
data
At ECHO- 1, average LV end-diastolic and end-systolic diameters and f&&on@ shiorten~g were 56.5 f 7.1 mm, 44.1 f 6.5 mm a& 21 .Q rt 4,7%, respectively. At ECHO-2 they wepe 52.3 i: 5.3 mm (P <. O.OOOl), 37.2 f 4.9 mm (P < O.@W) and 24.1 + 4.9% (P < O.OO;O-I>, respegtivety. Average infarctrelated territory score was 7.81 f 4.50 at ECHO-l, and 10.73 & 4.97 at ECHO-2 (P < O&01>, because of an increase of + 2.93 & 3.21 detected in 26 patients (70%). Rad.i+mmAide data
data
Average LV ejection fraction was 4 1% (range = 3552%). Anterior infarction was detected in 27 patients, whereas the remainder presented with inferior infarction. Infarct-related arteries presented with stenoses graded as < 90%, 90-99% and 100% in 9, 7 and 21 cases, respectively. Significant coronary stenoses were found on left anterior descending artery (LBD) in 35 patients, on left circumflex artery territory in 21 patients, and on right coronary artery (RCA) territory in 26 patients. Thus, 11 patients presented with 3-vessel disease, 21 with 2-vessel disease, and five w&h l-vessel disease, respectively. Collaterals to LAD were detected in 14 patients, and were graded as 1, 2 and 3 in 4, 8 and 2 cases, respectively. Collaterals to RCA were found in seven patients, and were gmded as 1, 2 and 3 in two, three and two cases, respectively (Table I). NTG
but in no case did NTG infusion have to be stopped because of side-effects. AH parameters recovered to basal values within 10 min from the end of NTG infusion.
APRIL
1998 VOL 6 NO 2
Average MIBI uptake score was 5.19 f 3.10 at MIBI-1, and 7.16 + 3.18 at MIBI-NTG, for an average increase of + 1.97 + 1.59 (P c’ 0.001) detected in 32 patients (86%) (Figure 1). MIBI-2 average score in the 36 patients studied was 7,81 + 2.47, for an average increase of + 2.62 f 1.80 (P < 0.001) detected in 31 patients (86%), in comparison with MIBI-1. NT&induced increase in MI&I up&e (Table 2) was significantly higher in rhe Ifs patients with collaterals score > 1 in comparia6#rs wi& patients with score 5 1 ( + 3.0 f 1.69 nm + 1.27 I 1.08, P < O.Ol), whereas wail motion dH+mces were not statistically signif&mt ( + 3.06 f 2.55 U~YSUS+ 2.64 rt 3.62, P = N.S.). A~~, out of five patients who did not improve Itpl;EBI upmke after NTG, four showed no collat&&~ and one had a significant stenosis on the vessel supplying collateral circulation. A positive change in LV wall motion after the operation (Table 3) was associated with a significantly higher change in MIBI uptake after NTG infusion ( + 2.31 + 1.64 verssus-t 1.10 i 1.20, P < 0.05). Also the change in MIBI uptake after operation was significantly higher in patients showing an increase in LV wall motion ( + 3.27 ? I .5 I ‘ZWSZLS + 0.60 + 0.70, I’ cc 0.001). IS1
NTG-induced
perfusional
changes
predict
viability:
C. Greco
et al.
MIBI-2
MIBI-NTG
MIBI-I
ANTERIOR
VIEW
LAO 45O VIEW
LAO 70° Figure 1 From left to right, preoperative basal (MIBI-1). preoperative 45” left anterior oblique (middle) and 70” left anterior oblique (bottom) and basal anteroseptal walls at MIBI-NTG scan is visible. Postoperative
VIEW
nitroglycerine (MIBI-NTG) and postoperative basal (MIBI-2) scans in anterior (top), views are shown. A clear-cut increase of tracer uptake on the anterior, anterolateral scans show increased tracer uptake in the same myocardial zones
CARDlOVA8CULAR
SURGERY
APRIL
1998
VOL 6 NO 2
NTG-induced Table 2 Different distribution of collateral circulation Collateral
circulation
NTG-induced
perfusional
yes (n = 32) 15 1’7
yes (n = 15) no (n = 22) NTG. nitroglycerine:
Table 3
of perfusional
done patient
Wall motion
improvernent
improvement
undergoing
perfusionai
NTG. nitroglycerine:
%ne patient
died before
wall motion
postoperative
radionuclide
infusion
and by revascularization
improvement
postoperative
improvement
predict
and revascularization.
viabi/i$ dependirig
Postoperative
perfusionai
I:. Greco
et al.
on the presence
imorovement” ---____
“b :,: : 5: ? 3 -...----II___
yes (n = 31) 13 18
in predicting
Postoperative yes (n = 311 24 ‘7 radionuclide
changes
study.
no (n = 5) 2 3 undergoing
Infusion
no (n = 11) 5 6
yes (n = 26) 10 16
changes induced by nitroglycerine
NTG-induced
by nitroglycerine
Postoperative
yes (n = 32) 24 8
yes in = 26) no (n = 11)
changes induced
no (n = 5) 0 5
died before
Accuracy of tracer uptake
and functional
perfusional
postoperative
perfusional
wall motion improvement _.-~_____
improvement’ no (V I: 2 3
rj
study.
The improvement of MIBI uptake after NTG infusion was correctly classified as viable in 24126 (92%) infarcted territories of patients showing wall motion improvement after operation, whereas 24/3 1 (77%) patients showing NTG-induced increase in MIBI uptake presented wall motion improvement postoperatively.
inhibition of oxidative phosphorylation reduces its uptake, and in the presence of severe post-ischaemic injury, both mitochondrial and plasma membrane depolarize, thereby decreasing rhe driving force for MIBI retention.
Discussion
Several tests have been coupled to radionuclide methods in an attempt to induce some changes compatible with myocardial viability, ranging from low dose dobutamine infusion[2 11, to a isometric stress test[22], or to NTG administration[23]. The latter acts through a direct effect on the coronary wall, as well as through systemic haemodynamic and metabolic effects, which have been widely documented in patients with coronary artery disease. In fact, nitrates are known to improve oxygen delivery to ischaemic areas by increasing total myocardial blood flow through stenotic coronary arteries and collateral circulation[24, 251. This is the result of the recruitment of a pre-existing collateral network, which is often abundant in myocardial zones supplied by occluded or nearly occluded vessels, as well as of the dilation of narrowed vessels at the level of epicardial eccentric stenoses and/or of muscular pre-arterioles. Additionally, the effects on preload and afterload induce a decrease in LV volume and wall tension, resulting in a reduction in myocardial oxygen requirements [ 121. The increase in blood supply provided by NIG i.v. infusion allows an increased MIBI delivery to akinetic areas, which can retent and concentrate it, as mentioned above, only if basal energy-depending mechanisms are still available, i.e. only if the cell is still viable.
It would be of major clinical interest to find a simple and repeatable method capable of predicting recovery of function in territories presenting with an abnormal wall motion, more likely to reflect irreversible dysfunction and scar. Many methodological approaches have been proposed and are currently tested, such as dobutamine echocardiography, fatty acid, 201T1 and MIBI scintigraphy, and positron emission tomography[2-6, 191. Tracer
characteristics
MIBI is a lipophilic cationic compound with high whose myocardial uptake myocardial affinity, depends on both blood flow and metabolic balance[9-111. In fact, MIBI capture is proportional to blood flow under a wide range of flows, but its retention depends on passive diffusion across both cellular and mitochondrial inner membranes in response to large negative transmembrane potentials. Thus, mitochondrial localization and further concentration of the tracer are favoured by intermediary metabolism of substrates delivering reducing equivalents to mitochondrial electron transfer cytocromes [9]. Experimental studies[20] showed MIBI accumulation to be dependent upon metabolic status, as the CARDIOVASCULAR
SURGERY
APRIL
1998
VOL 6 NO 2
Action
of nitrates
153
NTG-induced
Study
perfusional
changes
predict
viability:
C.
GreCO
et al.
results
Differently from previous investigators [26], who administered NTG orally, we preferred to use i.v. infusion, in order to obtain fast and short-lasting (< 10 min in our study) haemodynamic systemic and local effects. In this way we attempted to acquire basal and NTG perfusional scans in the same haemodynamic conditions, thus avoiding long-lasting improvements in left ventricular wall motion from oral NTG administration, which is eventually responsible for a partial volume effect[27]. The increased MIBI uptake detected in this study after NTG administration in infarcted segments suggests the capability of this method to identify viable but chronically hypoperfused myocardium. The presence of collateral circulation with high-degree retrograde filling allowed the best improvement of myocardial MIBI uptake to be obtained. These findings were confirmed by repeating radionuclide study after revascularization. The majority of areas supplied by collaterals and showing increased MIBI uptake after NTG infusion, presented with an improvement in LV wall motion at echocardiography after revascularization. Thus, possibly collateral vessels may be highly effective in maintaining a minimal myocardial perfusion and tissue viability, but may not be effective enough to preserve wall motion (hibernating myocardium). Prediction. of improvement in postoperative MIBI uptake was very accurate by using NTG infusion, possibly because NTG could determine a better distribution of tracer, oxygen and substrates to still viable cells, thus increasing myocardial uptake. Experimental studies[lO, 16, 26, 271 have suggested that cell viability is necessary for myocardial MIBI uptake and retention in the presence of adequate blood flow. Further evidence of that is provided by the close relation shown by MIBI-NTG and MIBI2 uptake changes in comparison with MIBI-1. Study
limitations
A limitation of the study is represented by the selection bias of such a small study group. Certainly the accuracy and clinical effectiveness of the method needs to be tested on larger patient groups, in order to draw pathophysiological and prognostic implications. Additionally, the simultaneous assessment of several variables, such as LV performance together with myocardial perfusion, or echocardiographic study during NTG administration, would possibly have clarified the behaviour of infarcted areas, as well as NTG infusion during coronary angiography, in order to discriminate the different contributions to the improvement in blood flow due to collaterals and to dilation of eccentrically narrowed coronary vessels. The same applies to a postoperative coronary
154
arteriographic study, which if performed, would have strengthened the conclusions of the study, confirming radionuclide perfusional results. MIBI scintigraphy during NTG infusion proved to be a useful, feasible and safe tool for the detection of viable myocardium in areas with abnormal kinesis, thus predicting wall motion and perfusion improvement after revascularization. At present, collaterals seem to represent the major independent variable related to viability, though future studies are necessary to rule out other anatomic and clinical parameters possibly conditioning it, such as the position, the degree as well as the morphology of coronary stenoses.
References 1. Rahimtoola, S., The hibernating myocardium. Anierican Heart journal, 1989, 117, 211-221. 2. Tillisch, J. H., Bnmken, R., Marshall, R. et al., Reversibility of cardiac wall motion abnormalities predicted by positron tomography. New England Journal of Medicine, 1986, 314, 884.-888. 3. Murray, G., Schad, N., Ladd, W. er al., Metabolic cardiac imaging in severe coronary disease: Assessment of viability with iodine-123-iodophenylpentadecanoic acid and multicrystal gamma camera, and correlation with biopsy. Journal of Nuclear Medicine, 1992, 33, 1269-1277. 4. Marzullo, I’., Parodi, O., Reisenhofer, B. et aZ., Value of rest thallium-201/technetium-99m Sestamibi scans and dobutamine echocardiography for detecting myocardial viability. America?r ~oumal of Cardiology, 1993, 71, 166-172. V. and Bonow, R. O., Current diagnostic technique of 5. Dilsizian, assessing myocardial viability in patients with hibernating and stunned myocardium. Circulation, 1993, 87, l-20. 6. Sawada, S., Allman, K., Muzik, 0. et al., Positron emission tomography detects evidence of viability in rest technetium-99m Sestamibi defects. Journal ojthe American College of Cardiology, 1994, 23, 92-98. 7. Ciavolella, IM., Tomai, F., Vicchio, D. et al., Single-day combined evaluation of regional myocardial perfusion and function at rest and neak exercise with 99mTcMIBI in natients with coronary artery disease. International Journal of Cardiac Imaging, 1993,9,99 111. J., Roy, L. T. et al., Comparison of tech8. Kiat, H., Maddahi, netium 99m methoxy isobutyl isonitrile and thallium 201 for evaluation of coronary artery disease by planar and tomographic methods. Anzerica?z Heart Journal, 1989, 117, l-l 1. 9. Freeman, I., Grunwald, A. M., Hoory, S. and Bodenheimer, M. M., Effect of coronary occlusion and myocardial viability on myocardial activity of technetium-99m-isonitrile. Journal of Nuclear Medicine, 1991, 32, 292-298. 10. Piwnica-Worms, D., Kronauge, J. F. and Chiu, M. L., Uptake and retention of hexakis (2-methoxyisobutyl isonitrile) Technetium(I) in cultured chick myocardial cells Mitochondrial and plasma membrane potential dependence.. Circulation, 1990, 82, 1826-1838. R. C., Silber, S. and Pohost, G. M., Relations of the 11. Canby, myocardial imaging agents 99mTc-MIBI and 201Tl to myocardial blood flow in a canine model of myocardial ischemic insult. Circulation, 1990, 81, 289-296. 12. Abrams, J., Mechanisms of action of the organic nitrates in the treatment of myocardial ischemia. American 3uurnal oj(2ardioloB, 1992, 70, 30B-4r2B. 13. Brown, B. G., Bolson, E. L., Peterson, R. B. et al., The mechanism of nitroglycerin action. Stenosis vasodilation as a major component of drug response. Circulation, 198 1, 65, 1089-l 097. 14. Jugdutt, B. J., Becker, L. C., Utchings, G. M. et al., Effect of
CARDIOVASCULAR
SURGERY
APRIL
1998 VOL 6 NO 2
NTG-induced
15
16
17
18
19
20
21
intravenous nitroglycerin on collateral blood flow and infarct size in the conscious dog. Circulation, 1981, 63, 17--28. Beanlands, R. S., Dawood, I;., Wen, W. et aZ., Are the kinetics of technetium-99m methoxyisobutyl isonitrile affected by cell metabolism and viability? Circulation, 1990, 82, 1802-1814. Crane, I’., Ialiberte, R., Heminway, S. ez al., Effect of mitochondnal viability and metabolism on technetium-99m-Sestamibi myocardial retention. Europem Journal of Nuclear Medicine, 1993, 20, X-25. Cohen, M. V. and Rentrop, K. P., Limitation of myocardial rschemia by collateral circulation during sudden controlled coronaty artery occlusion in human subjects: a prospective study. Circulutiou, 1986, 74, 469. 476. Schiller, !q. B., Shah, P. M., Crawford, M. ez ol., Recommendations for quantitation of 2-D echocardiography. 3oumal of the .~lnwicmz Socieq o.f Echocardiography, 1989, 2, 358-367. Barilla, F., Gheorgbiade, LU., Alam, H. et al., Low-dose dobutamine in patients with acute myocardial infarction identifies viable but not contractile myocardium and predicts the magnitude of improvement in wall motion abnormalities in response to coronary revascularization. Anzeti~7r Heart Journal, 1991, 122, 1522 1531. (:arvalho, I’. A., Chiu, M. I,., Kronauge, J. F. et al., Subcellular distribution and analysis of technetium-99m-MIBI in isolated perfused rat hearts. ,$unzui of ~Yuclear Medicine, 1992, 33, 1516 1521. Barilli, F., De Vincentis, G., Gemelli, F. et al., (1994)(abstr.) Functional recovery of viable myocardium with dobutamine
CARDIOVASCULAR
SURGERY
APRIL
1998 VOL 6 NO 2
22.
23.
24.
25.
26.
27.
perfusronal
changes
predict
viabi\iti/:
i: C%w
ez- a/.
stress echocardiography and 99mTcSesramibi upmk?. f~uropmr Heart Journal, 15, 435. Quinones, M. A., Gaasch, W. H., Watsser, E. ,.f ,z/., An analysis of the left ventricular response to isometric ~~xrrcisr .#~renc~r~ Hean 30urn4 1974, 88, 29--36. Tanzilli, G., Greco, C., Scopinaro, F. 2t ul., Enhanced detccticln of viable myocardium by 99mTc-MIBI imaging after nitratemediated vasodilation. Journal qf I\‘uc!em Htr&q~ md .Medicine. 1992, 136, 163-164. Winbury, IM. M., Redistribution of left ventricular blood flow produced by nitroglycerin. Circulation Ke.search, 197 1, B(Suppl. I), 140-147. Fujita, M., Yamanishi, K., Hirai, T. L’I cri., Significance of collateral circulation in reversible left ventricular asinergy bv nitroglycerin in patients with relatively recent myocardial innuction. American Heart Journal, 1990, 120, 521 538. Galli, M., &Marcassa, C., Imparato, A. ~‘r Gi.> Effxrs of nitroglycerin by Technetium-99m Sestamibi tomtlscmtigraphy on resting global myocardial hypoperfusion in stable patients with healed myocardial infarction. Rmericcz?l ,@~i& lli t :/&io~o~~, 1994, 74, 843-848. Sinusas, A. J., Shi, Q,, Vitols, P. J. t?z oi., Impact ot regional ventricular function, geometry, and dobutaminr stress on quantitative 99mTc-Sestamibi defect size. Cir&,&~~i. ! 0173. 8X. 2224 2234.
Paper
accepted
lo October
1997
15s