- Email: [email protected]
Experimental studies of the physiologic properties of technetium-99m isonitriles
Experimental Studies of the Physiologic Properties of Technetiumm99m lsonitriles George A. Belier, MD, and Albert J. Sinusas. MD
ntly, efforts have been directed at the developof technetium-99m (Tc-99m)-labeled isonitrile compounds for assessment of regional perfusion and viability after experimental myocardial infarction or ischemia. One of the most promising of these agents, Tc-99m sestamibi, has undergone rather extensive laboratory investigation. Like thallium-201 (TI-201), the uptake of Tc-99m sestamibi in myocardial tissue is proportional to myocardial blood flow after intravenous injection. Similar to other diffusible indicators, Tc-99m sestamibi underestimates blood flow at high flow rates. In low flow regions, the myocardial uptake of this agent is higher relative to nonischemic uptake than is microsphere-determined blood flow. This is attributed to increased extraction at low flows. This first-pass myocardial extraction fraction for Tc-99m sestamibi is less than that for 11-201. However, Tc-99m sestamibi has a higher parenchymal cell permeability and higher volume of distribution than 11-201. Tc-99m sestamibi shows minimal “delayed redistribution” after initial intravenous administration. Uptake of Tc-99m sestamibi is not altered by myocardial “stunning” or with ischemic dysfunction produced by sustained low coronary flow. The uptake of the isonitrile is still proportional to blood flow in these situations. In intact animal models, myocardial uptake of Tc-99m sestamibi during coronary occlusion delineates the in vivo area at risk. When Tc-99m sestamibi is administered after reperfusion following variable periods of preceding coronary occlusion, Tc-99m sestamibi uptake delineates the area of viable myocardium that is salvaged and not simply the degree of reflow. This suggests that serial Tc99m sestamibi imaging might be useful in assessing the efficacy of coronary reperfusion after thrombolytic therapy. (Am J Cardiol f998;66:5L-
From the Cardiology Division, Department of Medicine, University of Virginia Health Sciences Center, Charlottesville, Virginia. This study was supported in part by grant ROl HL-26205 from the National Heart, Lung, and Blood Institute, Bethesda, Maryland, and a grant from the E. I. Du Pont de Nemours & Co., North Billerica, Massachusetts. Dr. Sinusas’s current address: Yale University School of Medicine, 333 Cedar St.-TE-2, New Haven, Connecticut 0651043056. Address for reprints: George A. Beller, MD, Box 158, Division of Cardiology, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908.
nrecentyears,newtechnetium-99m(Tc-99m)-labeled myocardial perfusion agents have beenunder laboratory and clinical investigation to determine their efficacy in evaluating regional myocardial blood flow and viability. More recently, efforts have been directed at the development of Tc-99m-labeled isonitrile compoundsfor the assessmentof regional perfusion and viability after experimental myocardial infarction or ischemia either during sustained coronary occlusion or after reperfusion. One of the most promising of these agents is Tc-99mhexakis-2-methoxy-2-methylpropyl isonitrile (Tc-99m sestamibi), which is a lipophilic cationic Tc-99m complex that has the most favorable myocardial-to-background ratio for myocardial imaging of any of the isonitriles. The uptake and clearance kinetics of this new myocardial agent have beeninvestigated in a number of experimental animal models. INITIAL MYOCARDIAL DlSTF?lBUTlON TECHNETIUM-99m SESTAMIBI
OF
Myocardial uptake of Tc-99m sestamibi occurs in proportion to myocardial blood fl~w.“~~This property is similar to that of thallium-201 (Tl-201). Okada et al’ demonstrated a good correlation (r = 0.92) between microsphere-determined myocardial blood flow and Tc99m sestamibi distribution using anesthetized dogs undergoing partial left circumflex coronary artery occlusion (Fig. 1). In a similar animal model, Glover and Okada demonstrated a linear relation (r = 0.97) between the initial myocardial uptake of Tc-99m sestamibi and regional myocardial blood flow at rates up to 2.0 ml/min/g when the agent was administered after an intravenous infusion of dipyridamole (Fig. 2). However, like other diffusible indicators, Tc-99m sestamibi was shown to underestimate myocardial blood flow at high flow rates (>2.0 ml/min/g). Li and coworkers3 showed that the myocardial distribution of Tc-99m sestamibi, as quantified from short-axis tomograms using a computerized circumferential profiles program, corresponded to regional myocardial perfusion by radioactive microspheres. After coronary reperfusion, Tc-99m sestamibi uptake in the center of the previously ischemic zone correlated well with recovery of flow as measured by the radioactive microsphere technique. The tomographic images showed resolution of the perfusion defect in all animals in which reperfusion was successful. In low flow regions, the myocardial uptake of Tc-99m sestamibi is higher relative to nonischemic uptake than is the microsphere-determined regional blood flo~.~,~JThis is attributed to the increased extraction of this agent at low flows comparable to what has been observed with
THE AMERICAN JOURNAL OF CARDIOLOGY
OCTOBER 16.1990
A SYMPOSIUM:
TECHNETIUM-99m
IMAGING
AGENTS
uptake of the 2 agents when imaged in vivo. This is becausecapillary permeability for Tl-201 is higher than Tc-99m sestamibi but the reverseis true at the parenchyma1 cell wall. In another study by Meerdink and Lepposusing the sameblood-perfusedisolated rabbit heart model,hypoxia and ouabain had minor effects on peak myocardial extraction and the permeability-surface areaproduct of Tc99m sestamibi. Maublant et al9 showed,in myocardial Y = 31.03X + 4.22 cells in culture, that cyanide and iodoacetate(which pror = 0.92 foundly affect myocardial metabolism by inhibiting the I I I I I 0 respiratory chain and glycolysis, respectively), did not 0 0.2 0.4 0.6 0.6 1.0 affect Tc-99m sestamibi uptake and efflux, even in the Myocardlal Flow (mliminlg) presenceof impaired contractile function. However, TlFIGURE 1. Relation of initial (microsphere) myocardial blood 201 uptake was inhibited by the combination of cyanide flow to technetium99m (Tc-99m) sestamibi distribution. and iodoacetate. Ouabain inhibition of sodium, potassiThere is a linear relation with an r value of 0.92 (reproduced um, adenosinetriphosphatase also had no effect on Tcby permission of the American Heart Association’). 99m sestamibi, but did affect Tl-201. Thus, it appears from thesein vitro and in vivo experimental preparations radionuclide monovalent cations such as Tl-201. Canby that the uptake mechanismsof Tc-99m sestamibiare less et al* showed a close positive linear correlation between dependenton active transport processesthan are thoseof Tc-99m activity and microsphere-determined blood flow Tl-201. Intracellular extraction of Tc-99m sestamibican when Tc-99m sestamibi was given before reflow at the proceed even with rather profound metabolic perturbaend of a 2-hour coronary occlusion interval. According to tions as long as the cell membrane is intact and cellular their data, there would be an excessof Tc-99m sestamibi viability exists. above the level predicted on the basis of blood flow in zones where flow was reduced by approximately 10 to MYOCARDIAL CLEARANCE OF 40% of control flow. This observation was interpreted as TECHNETIUM-99m SESTAMIBI Tc-99m sestamibi showsnegligible “delayed redistriincreased extraction by viable myocardium during the 40-minute interval and not construed as being consistent bution” after initial intravenous administration. Okada et with delayed redistribution. However, when flow de- al’ assessedclearance of Tc-99m sestamibiin dogs subcr;ased to between 0 and 10% of control, this increased jected to circumflex coronary artery stenoses.Myocardiextraction relative to flow was not evident. This was inter- al Tc-99m sestamibi activity in ischemicand nonischemic preted as being consistent with the reduced ability of zones was continuously monitored with miniature iminfarcted nonviable myocardium to extract the tracer. plantable radiation detectorsfor 4 hours after injection of Thus, these animals studies suggestthat myocardial up- the radionuclide. In this model of severelow flow ischtake of Tc-99m sestamibi is proportional to regional flow emia, the fractional Tc-99m sestamibi clearanceover 4 in the physiologic flow range with enhancedextraction of hours was minimal in the ischemic (15 f 7%) and nonthe tracer in low flow regions where myocardium is still ischemic (15 f 5%) zones.Thesedata suggestthat there viable. As expected,there is an inverserelation betweencoronary blood flow and the fractional extraction of Tc-99m % Normal activity (x100) 5.00 sestamibi. The first-pass myocardial extraction fraction for Tc-99m sestamibi is lessthan that for Tl-201. Studies 4,00 _ -Identity line 0 Y=o.12+0.66(x) r=o.97 by Leppo and Meerdink7 in the blood-perfused isolated rabbit heart showedthat the mean peak value during the 3.00 early plateau phaseof extraction (E,,,) for Tc-99m sestamibi (0.39) was significantly less than the mean E,,, 2.00 for Tl-201 (0.73) (Fig. 3). The net myocardial extraction (E,,& an estimate of myocardial retention, averaged0.41 for Tc-99m sestamibi and 0.57 for Tl-201. Tl-201 was shown to have a higher transcapillary exchange rate than I 0.00 1.00 2.00 3.00 4.00 5.00 Tc-99m sestamibi. The mean capillary permeability-surMyocardial flow (mliminig) face area product for Tc-99m sestamibi was approximately 33% of the value for Tl-201 (0.44 vs 1.30, respec- FIGURE 2. Scatterplot showing technetium-99m (Tc-99m) tively), but Tc-99m sestamibi had a significantly higher sestamibi activity (percent of normal zone activity) distribution myocardial blood flow after parenchymal cell permeability and higher volume of dis- versus microsphere-determined Tc-99m sestamibi distribution is linearly related tribution than Tl-201. The overall effect of these differ- todipyridamole; flow, up to approximately 2.9 ml/min/g. At higher flow encesin kinetics between Tc-99m sestamibi and Tl-201 is rates, Tc-99m sestamibi distribution underestimates flow (rethat little difference would be observedin the myocardial produced by permission of the American. Heart Associations). Decay 30 t-
6E
Corrected
Tc-99m
Activity
(x104CPM1g)
THE AMERICAN JOURNAL OF ClyRDlOLOGY
VOLUME 66
is no appreciable redistribution of Tc-99m sestamibi, which is in contrast to the significant delayed redistribution seen with Tl-201 in similar canine experimental models. This important difference can probably be explained by at least 2 characteristics of Tc-99m sestamibi: (1) low blood levels of Tc-99m sestamibi, and (2) long myocardial retention. The result of both is that little Tc99m sestamibi is available for reaccumulation.
% Non-lschemic 100 OOcclusion
r
EFFECT OF ISCHEMIA AND POSTISCHEMIC DYSFUNCTION ON TECHNETIUM-SSm SESTAMIBI UPTAKE
We have shown that administration of Tc-99m sestamibi during reperfusion precededby 15 minutes of transient coronary occlusion resulted in normal uptake of the radionuclide in the region of myocardial “stunning.“5 Uptake of Tc-99m sestamibi in this model of stunned myocardium was comparable to uptake of Tl-201 and proportional to regional blood flow (Fig. 4). Our group also assessedthe myocardial uptake of Tc99m sestamibi and Tl-201 under conditions of a chronic low flow statein an anesthetizedopen-chestcanine model producing ischemic dysfunction.5 As shown in Figure 5, central ischemic Tc-99m sestamibi activity and Tl-201 activity (expressedas a percentageof the activity in the correspondingnonischemiczone) were comparablein endocardial and epicardial segments and proportional to flow at the time of tracer injection. These endocardial segmentsshoweda good linear correlation between flow and activity of both Tl-201 (r = 0.78) and Tc-99m sestamibi (r = 0.85). It can be concluded from these studies that ischemia, which produces profound systolic dysfunction, does not affect Tc-99m sestamibi or Tl-201 uptake as long as myocardial cells are still viable. Despite significant ischemia or postischemicsystolic dysfunction in thesemodels, the uptake of theseradionuclides was still proportional to flow at the time of their administration. There was no flow-independent abnormality in myocardial uptake in
Extraction 1.0
Flow
tiwFteperfusion -
IThalliumC3Tc-99m -
Sestamibi
7
T
Intermediate lschemic
Central lschemic L
FlGURE 4. Regional blood flow and myocardial activity. Illustrated are occlusion and reperfusion flow and thallium-201 and technetium-BBm (Tc-SSm) sestamibi activity for central ischemic (n = 29) and intermediate ischemic (II = 21) endocardial segments expressed as a percent of nonischemic segmental flow. Roth thallium-201 and Tc-99m sestamibi activity levels were comparable with reperfusion flow in central and intermediate ischemic segments (reproduced by permission of the American College of Cardiology5).
the ischemic or “stunned” myocardial tissue. This lends support to the concept that Tc-99m sestamibi can be extracted intracellularly as long as cell membrane integrity is intact. QUANTIFICATION OF RISK AREA DURING CORONARY OCCLUSION AND MYOCARDIAL SALVAGE AFTER REPERFUSION USING TECHNETIUM-99m SESTAMIBI
Several studies have beenperformed to assesswhether myocardial imaging with Tc-99m sestamibi is useful for assessingrisk area during coronary occlusion and extent of salvaged myocardium after coronary occlusion followed by reperfusion. Verani and coworkers4found that the scintigraphic perfusion defect size correlated well with pathologic infarct size (r = 0.85 and r = 0.95 by planar and tomographic imaging, respectively) during 2
(Emax)
r
Thallium-201 Tc-99m Sestamibi
0 I
0.0 0.0
1.0
2.0 Flow (mliminig)
GURE 3. Comparison of t~bneti~m-BBm ibi and thallium-201 (R-201) extraction coronary blood flow. Linear least-squares shown; the top line represents +c Bottom line represents R-201 (re the Arne~~n Reart Ass~iat~a~~).
3.0
20
(Tc-BSm) sesta(E,,,) values versus regression Iines are tamibi, and the by permission of
(TI-201) (Tc-99m
y = 0.87X + 22 y = 0.95x + 17
Sestamibi) I
I
40 60 Flew (% Nonischemic)
80
I
r = 0.76 r = 0.85 I
100
FIGURE 5. Central ischemic endocardial activity versus flow. lllustrated is the correlation of thallium-201 (R-201) and technetium-BBm (lc-BBm) sestamibi activity and stenotic Row among those endocardial segments in which stenotic flow was reduced to
THE AMERICAN JOURNAL OF CARDIOLOGY
OCTOBER 16,199O
A SYMPOSIUM:
TECHNETHJM89m
IMAGING
AGENTS
% LV 40
p
I
’
Scintigraphic
Planar
FTC) I
FIGURE 6. Comparison of planar scintigraphic perfusion defect size during occlusion and repetiusion with pathologic infarct size in 12 dogs. LV = left ventricle; lTC = triphenyltetrazolium chloride (reproduced by permission of the American College of Cardiology4).
Thus, the results of theseanimal studiesindicate that the myocardial uptake of Tc-99m sestamibiduring coronary occlusion correlates with occlusion flow and delineatesthe in vivo “area at risk.” When Tc-99m sestamibi is given after reperfusion following variable periods of preceding coronary occlusion, Tc-99m sestamibiactivity uptake delineates the area of viable myocardium that is salvaged,with defectsizecorrelating well with pathologic infarct size. Thesedata are consistentwith clinical imaging studies that have shownthat serial Tc-99m sestamibi imaging is useful in assessingthe efficacy of coronary reperfusion in patients receiving thrombolytic therapy.“J2 The experimental studiessuggestthat in the presenceof acute infarction, Tc-99m sestamibiuptake during reperfusion reflects both the degree of reflow and the extent of viable myocardium. Hence, its properties are not simply akin to inert microspheresthat merely measure regional myocardial blood flow after reperfusion.
hours of coronary occlusion in a canine model. The planar REFERENCES defect size, but not the tomographic defect size, overesti- 1. Okada RD, Glover D, Gaffney T, Williams S. Myocardial kinetics of techneCirculation mated the pathologic size. After 48 hours of reperfusion, tium-99m-hexakis-2-methoxv-2-methvluroov~-isonitri~e. 1988;77:491-498. scintigraphic defect size was markedly reduced. Uptake 2. Canby RC, Silber S, Pohost GM. Relations of the myocardial imaging agents of Tc-99m sestamibi in ischemic myocardium increased g9’“Tc-MIBI and *O’TI to myocardial blood flow in a canine model of myocardial ischemic insult. Circulation 1990;81:289-296. significantly and correlated with the increase in regional 3. Li Q-S, Frank TL, Franceschi D, Wagner HN Jr, Becker LC. Technetiumflow as assessedby microspheres.Figure 6 comparesthe 99m methoxyisobutyl isonitrile (RP30) for quantification of myocardial ischemia reperfusion in dogs. J Nucl Med 1988;29:1539-1548. planar scintigraphic defect size during occlusion and re- 4.andVerani MS, Jeroudi MO, Mahmarian JJ, Boyce TM, Barges-Neto S, Pate1 perfusion with the pathologic infarct size in 12 dogs in B, Bolli R. Quantification of myocardial infarction during coronary occlusion and myocardial salvage after reperfusion using cardiac imaging with technetiumthis study. hexakis 2.methoxyisobutyl isonitrile. J Am Co11 Car-dial 1988;12:1573More recently, we have defined in our laboratory the 99m 1581. myocardial distribution of Tc-99m sestamibi before and 5. Sinusas AJ, Watson DD, Cannon JM Jr, Belier GA. Effect of ischemia and dysfunction on myocardial aptake of technetium-99m-labeled after coronary reperfusion in open-chest anesthetized postischemic methoxyisobutyl isonitrile and thallium-201. J Am Coil Cardiol 1989;14:1785dogs that underwent 3 hours of left anterior descending 1793. occlusion followed by 3 hours of reflow. lo When intrave- 6. Glover DK, Okada RD. Myocardial kinetics of Tc-MIBI in canine myocardiafter dipyridamole. Circulation 1990;8 1:628&636. nous Tc-99m sestamibi was administered during occlu- 7.urnLeppo JA, Meerdink DJ. Comparison of the myocardial uptake of a technesion only, the risk area defined by autoradiography corre- tium-labeled isonitrile analogue and thallium. Circ Res 1989;65:632-639. lated (r = 0.94) with the postmortem risk area, although 8. Meerdink DJ, Leppo JA. Comparison of hypoxia and ouabain effects on the uptake kinetics of technetium99m hexakis 2-methoxy-isobutyl isoniit was somewhat smaller. This was thought to be due to myocardial trile and thallium-201. J Nucl Med 1989;30:1500-1506. the presenceof collateral flow in vivo, which would not 9. Maublant JC, Gachon P, Moins N. Hexakis (2-methoxy isobutylisonitrile) influence the postmortem risk area. In dogs receiving Tc- technetium-99m and thallium-201 chloride: uptake and release in cultured myocardial cells. J Nucl Med 1988;29:48%54. 99m sestamibi 90 minutes after coronary reperfusion that 10. Sinusas AJ, Trautman KA, Bergin JD, Watson DD, Ruiz M, Smith WH, was precededby 3 hours of occlusion, To99m sestamibi Belier GA. Quantification of “area at risk” during coronary occlusion and degree myocardial salvage after reperfusion with technetium99m methoxyisobutyl activity was less than reperfusion flow. The defect area ofisonitrile. Circulation in press. defined by Tc-99m sestamibi autoradiography correlated 11. Wackers FJTh, Gibbons RJ, Verani MS, Kayden DS, Pellikka PA, Behrenclosely with the postmortem infarct size (r = 0.98) in beck T, Mahmarian JJ, Zaret BL. Serial quantitative planar technetium-99m imaging in acute myocardial infarction: efficacy for noninvasive assessthese reperfused dogs, as assessedby the dual simulta- isonitrile ment of thrombolytic therapy. J Am Co/l Car&l 1989;14:861&873. neousperfusion of monastral blue into the left main coro- 12. Gibbons RJ, Verani MS, Behrenbeck T, Pellikka PA, O’Connor MK, Mahnary artery and triphenyltetrazolium chloride into the marian JJ, Chesebro JH, Wackers FJ. Feasibility of tomographic 99mTc-hexakis2-methoxy-2-methylpropyl-isonitrile imaging for the assessment of myocardial left anterior descendingartery distal to the occlusion un- area at risk and the effect of treatment in acute myocardial infarction. Circulation 1989;80:1277-1286. der physiologic pressures. I.
SE
THE AMERICAN JOURNAL OF CARDIOLOGY
VOLUME 66
.I
ntly, efforts have been directed at the developof technetium-99m (Tc-99m)-labeled isonitrile compounds for assessment of regional perfusion and viability after experimental myocardial infarction or ischemia. One of the most promising of these agents, Tc-99m sestamibi, has undergone rather extensive laboratory investigation. Like thallium-201 (TI-201), the uptake of Tc-99m sestamibi in myocardial tissue is proportional to myocardial blood flow after intravenous injection. Similar to other diffusible indicators, Tc-99m sestamibi underestimates blood flow at high flow rates. In low flow regions, the myocardial uptake of this agent is higher relative to nonischemic uptake than is microsphere-determined blood flow. This is attributed to increased extraction at low flows. This first-pass myocardial extraction fraction for Tc-99m sestamibi is less than that for 11-201. However, Tc-99m sestamibi has a higher parenchymal cell permeability and higher volume of distribution than 11-201. Tc-99m sestamibi shows minimal “delayed redistribution” after initial intravenous administration. Uptake of Tc-99m sestamibi is not altered by myocardial “stunning” or with ischemic dysfunction produced by sustained low coronary flow. The uptake of the isonitrile is still proportional to blood flow in these situations. In intact animal models, myocardial uptake of Tc-99m sestamibi during coronary occlusion delineates the in vivo area at risk. When Tc-99m sestamibi is administered after reperfusion following variable periods of preceding coronary occlusion, Tc-99m sestamibi uptake delineates the area of viable myocardium that is salvaged and not simply the degree of reflow. This suggests that serial Tc99m sestamibi imaging might be useful in assessing the efficacy of coronary reperfusion after thrombolytic therapy. (Am J Cardiol f998;66:5L-
From the Cardiology Division, Department of Medicine, University of Virginia Health Sciences Center, Charlottesville, Virginia. This study was supported in part by grant ROl HL-26205 from the National Heart, Lung, and Blood Institute, Bethesda, Maryland, and a grant from the E. I. Du Pont de Nemours & Co., North Billerica, Massachusetts. Dr. Sinusas’s current address: Yale University School of Medicine, 333 Cedar St.-TE-2, New Haven, Connecticut 0651043056. Address for reprints: George A. Beller, MD, Box 158, Division of Cardiology, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908.
nrecentyears,newtechnetium-99m(Tc-99m)-labeled myocardial perfusion agents have beenunder laboratory and clinical investigation to determine their efficacy in evaluating regional myocardial blood flow and viability. More recently, efforts have been directed at the development of Tc-99m-labeled isonitrile compoundsfor the assessmentof regional perfusion and viability after experimental myocardial infarction or ischemia either during sustained coronary occlusion or after reperfusion. One of the most promising of these agents is Tc-99mhexakis-2-methoxy-2-methylpropyl isonitrile (Tc-99m sestamibi), which is a lipophilic cationic Tc-99m complex that has the most favorable myocardial-to-background ratio for myocardial imaging of any of the isonitriles. The uptake and clearance kinetics of this new myocardial agent have beeninvestigated in a number of experimental animal models. INITIAL MYOCARDIAL DlSTF?lBUTlON TECHNETIUM-99m SESTAMIBI
OF
Myocardial uptake of Tc-99m sestamibi occurs in proportion to myocardial blood fl~w.“~~This property is similar to that of thallium-201 (Tl-201). Okada et al’ demonstrated a good correlation (r = 0.92) between microsphere-determined myocardial blood flow and Tc99m sestamibi distribution using anesthetized dogs undergoing partial left circumflex coronary artery occlusion (Fig. 1). In a similar animal model, Glover and Okada demonstrated a linear relation (r = 0.97) between the initial myocardial uptake of Tc-99m sestamibi and regional myocardial blood flow at rates up to 2.0 ml/min/g when the agent was administered after an intravenous infusion of dipyridamole (Fig. 2). However, like other diffusible indicators, Tc-99m sestamibi was shown to underestimate myocardial blood flow at high flow rates (>2.0 ml/min/g). Li and coworkers3 showed that the myocardial distribution of Tc-99m sestamibi, as quantified from short-axis tomograms using a computerized circumferential profiles program, corresponded to regional myocardial perfusion by radioactive microspheres. After coronary reperfusion, Tc-99m sestamibi uptake in the center of the previously ischemic zone correlated well with recovery of flow as measured by the radioactive microsphere technique. The tomographic images showed resolution of the perfusion defect in all animals in which reperfusion was successful. In low flow regions, the myocardial uptake of Tc-99m sestamibi is higher relative to nonischemic uptake than is the microsphere-determined regional blood flo~.~,~JThis is attributed to the increased extraction of this agent at low flows comparable to what has been observed with
THE AMERICAN JOURNAL OF CARDIOLOGY
OCTOBER 16.1990
A SYMPOSIUM:
TECHNETIUM-99m
IMAGING
AGENTS
uptake of the 2 agents when imaged in vivo. This is becausecapillary permeability for Tl-201 is higher than Tc-99m sestamibi but the reverseis true at the parenchyma1 cell wall. In another study by Meerdink and Lepposusing the sameblood-perfusedisolated rabbit heart model,hypoxia and ouabain had minor effects on peak myocardial extraction and the permeability-surface areaproduct of Tc99m sestamibi. Maublant et al9 showed,in myocardial Y = 31.03X + 4.22 cells in culture, that cyanide and iodoacetate(which pror = 0.92 foundly affect myocardial metabolism by inhibiting the I I I I I 0 respiratory chain and glycolysis, respectively), did not 0 0.2 0.4 0.6 0.6 1.0 affect Tc-99m sestamibi uptake and efflux, even in the Myocardlal Flow (mliminlg) presenceof impaired contractile function. However, TlFIGURE 1. Relation of initial (microsphere) myocardial blood 201 uptake was inhibited by the combination of cyanide flow to technetium99m (Tc-99m) sestamibi distribution. and iodoacetate. Ouabain inhibition of sodium, potassiThere is a linear relation with an r value of 0.92 (reproduced um, adenosinetriphosphatase also had no effect on Tcby permission of the American Heart Association’). 99m sestamibi, but did affect Tl-201. Thus, it appears from thesein vitro and in vivo experimental preparations radionuclide monovalent cations such as Tl-201. Canby that the uptake mechanismsof Tc-99m sestamibiare less et al* showed a close positive linear correlation between dependenton active transport processesthan are thoseof Tc-99m activity and microsphere-determined blood flow Tl-201. Intracellular extraction of Tc-99m sestamibican when Tc-99m sestamibi was given before reflow at the proceed even with rather profound metabolic perturbaend of a 2-hour coronary occlusion interval. According to tions as long as the cell membrane is intact and cellular their data, there would be an excessof Tc-99m sestamibi viability exists. above the level predicted on the basis of blood flow in zones where flow was reduced by approximately 10 to MYOCARDIAL CLEARANCE OF 40% of control flow. This observation was interpreted as TECHNETIUM-99m SESTAMIBI Tc-99m sestamibi showsnegligible “delayed redistriincreased extraction by viable myocardium during the 40-minute interval and not construed as being consistent bution” after initial intravenous administration. Okada et with delayed redistribution. However, when flow de- al’ assessedclearance of Tc-99m sestamibiin dogs subcr;ased to between 0 and 10% of control, this increased jected to circumflex coronary artery stenoses.Myocardiextraction relative to flow was not evident. This was inter- al Tc-99m sestamibi activity in ischemicand nonischemic preted as being consistent with the reduced ability of zones was continuously monitored with miniature iminfarcted nonviable myocardium to extract the tracer. plantable radiation detectorsfor 4 hours after injection of Thus, these animals studies suggestthat myocardial up- the radionuclide. In this model of severelow flow ischtake of Tc-99m sestamibi is proportional to regional flow emia, the fractional Tc-99m sestamibi clearanceover 4 in the physiologic flow range with enhancedextraction of hours was minimal in the ischemic (15 f 7%) and nonthe tracer in low flow regions where myocardium is still ischemic (15 f 5%) zones.Thesedata suggestthat there viable. As expected,there is an inverserelation betweencoronary blood flow and the fractional extraction of Tc-99m % Normal activity (x100) 5.00 sestamibi. The first-pass myocardial extraction fraction for Tc-99m sestamibi is lessthan that for Tl-201. Studies 4,00 _ -Identity line 0 Y=o.12+0.66(x) r=o.97 by Leppo and Meerdink7 in the blood-perfused isolated rabbit heart showedthat the mean peak value during the 3.00 early plateau phaseof extraction (E,,,) for Tc-99m sestamibi (0.39) was significantly less than the mean E,,, 2.00 for Tl-201 (0.73) (Fig. 3). The net myocardial extraction (E,,& an estimate of myocardial retention, averaged0.41 for Tc-99m sestamibi and 0.57 for Tl-201. Tl-201 was shown to have a higher transcapillary exchange rate than I 0.00 1.00 2.00 3.00 4.00 5.00 Tc-99m sestamibi. The mean capillary permeability-surMyocardial flow (mliminig) face area product for Tc-99m sestamibi was approximately 33% of the value for Tl-201 (0.44 vs 1.30, respec- FIGURE 2. Scatterplot showing technetium-99m (Tc-99m) tively), but Tc-99m sestamibi had a significantly higher sestamibi activity (percent of normal zone activity) distribution myocardial blood flow after parenchymal cell permeability and higher volume of dis- versus microsphere-determined Tc-99m sestamibi distribution is linearly related tribution than Tl-201. The overall effect of these differ- todipyridamole; flow, up to approximately 2.9 ml/min/g. At higher flow encesin kinetics between Tc-99m sestamibi and Tl-201 is rates, Tc-99m sestamibi distribution underestimates flow (rethat little difference would be observedin the myocardial produced by permission of the American. Heart Associations). Decay 30 t-
6E
Corrected
Tc-99m
Activity
(x104CPM1g)
THE AMERICAN JOURNAL OF ClyRDlOLOGY
VOLUME 66
is no appreciable redistribution of Tc-99m sestamibi, which is in contrast to the significant delayed redistribution seen with Tl-201 in similar canine experimental models. This important difference can probably be explained by at least 2 characteristics of Tc-99m sestamibi: (1) low blood levels of Tc-99m sestamibi, and (2) long myocardial retention. The result of both is that little Tc99m sestamibi is available for reaccumulation.
% Non-lschemic 100 OOcclusion
r
EFFECT OF ISCHEMIA AND POSTISCHEMIC DYSFUNCTION ON TECHNETIUM-SSm SESTAMIBI UPTAKE
We have shown that administration of Tc-99m sestamibi during reperfusion precededby 15 minutes of transient coronary occlusion resulted in normal uptake of the radionuclide in the region of myocardial “stunning.“5 Uptake of Tc-99m sestamibi in this model of stunned myocardium was comparable to uptake of Tl-201 and proportional to regional blood flow (Fig. 4). Our group also assessedthe myocardial uptake of Tc99m sestamibi and Tl-201 under conditions of a chronic low flow statein an anesthetizedopen-chestcanine model producing ischemic dysfunction.5 As shown in Figure 5, central ischemic Tc-99m sestamibi activity and Tl-201 activity (expressedas a percentageof the activity in the correspondingnonischemiczone) were comparablein endocardial and epicardial segments and proportional to flow at the time of tracer injection. These endocardial segmentsshoweda good linear correlation between flow and activity of both Tl-201 (r = 0.78) and Tc-99m sestamibi (r = 0.85). It can be concluded from these studies that ischemia, which produces profound systolic dysfunction, does not affect Tc-99m sestamibi or Tl-201 uptake as long as myocardial cells are still viable. Despite significant ischemia or postischemicsystolic dysfunction in thesemodels, the uptake of theseradionuclides was still proportional to flow at the time of their administration. There was no flow-independent abnormality in myocardial uptake in
Extraction 1.0
Flow
tiwFteperfusion -
IThalliumC3Tc-99m -
Sestamibi
7
T
Intermediate lschemic
Central lschemic L
FlGURE 4. Regional blood flow and myocardial activity. Illustrated are occlusion and reperfusion flow and thallium-201 and technetium-BBm (Tc-SSm) sestamibi activity for central ischemic (n = 29) and intermediate ischemic (II = 21) endocardial segments expressed as a percent of nonischemic segmental flow. Roth thallium-201 and Tc-99m sestamibi activity levels were comparable with reperfusion flow in central and intermediate ischemic segments (reproduced by permission of the American College of Cardiology5).
the ischemic or “stunned” myocardial tissue. This lends support to the concept that Tc-99m sestamibi can be extracted intracellularly as long as cell membrane integrity is intact. QUANTIFICATION OF RISK AREA DURING CORONARY OCCLUSION AND MYOCARDIAL SALVAGE AFTER REPERFUSION USING TECHNETIUM-99m SESTAMIBI
Several studies have beenperformed to assesswhether myocardial imaging with Tc-99m sestamibi is useful for assessingrisk area during coronary occlusion and extent of salvaged myocardium after coronary occlusion followed by reperfusion. Verani and coworkers4found that the scintigraphic perfusion defect size correlated well with pathologic infarct size (r = 0.85 and r = 0.95 by planar and tomographic imaging, respectively) during 2
(Emax)
r
Thallium-201 Tc-99m Sestamibi
0 I
0.0 0.0
1.0
2.0 Flow (mliminig)
GURE 3. Comparison of t~bneti~m-BBm ibi and thallium-201 (R-201) extraction coronary blood flow. Linear least-squares shown; the top line represents +c Bottom line represents R-201 (re the Arne~~n Reart Ass~iat~a~~).
3.0
20
(Tc-BSm) sesta(E,,,) values versus regression Iines are tamibi, and the by permission of
(TI-201) (Tc-99m
y = 0.87X + 22 y = 0.95x + 17
Sestamibi) I
I
40 60 Flew (% Nonischemic)
80
I
r = 0.76 r = 0.85 I
100
FIGURE 5. Central ischemic endocardial activity versus flow. lllustrated is the correlation of thallium-201 (R-201) and technetium-BBm (lc-BBm) sestamibi activity and stenotic Row among those endocardial segments in which stenotic flow was reduced to
THE AMERICAN JOURNAL OF CARDIOLOGY
OCTOBER 16,199O
A SYMPOSIUM:
TECHNETHJM89m
IMAGING
AGENTS
% LV 40
p
I
’
Scintigraphic
Planar
FTC) I
FIGURE 6. Comparison of planar scintigraphic perfusion defect size during occlusion and repetiusion with pathologic infarct size in 12 dogs. LV = left ventricle; lTC = triphenyltetrazolium chloride (reproduced by permission of the American College of Cardiology4).
Thus, the results of theseanimal studiesindicate that the myocardial uptake of Tc-99m sestamibiduring coronary occlusion correlates with occlusion flow and delineatesthe in vivo “area at risk.” When Tc-99m sestamibi is given after reperfusion following variable periods of preceding coronary occlusion, Tc-99m sestamibiactivity uptake delineates the area of viable myocardium that is salvaged,with defectsizecorrelating well with pathologic infarct size. Thesedata are consistentwith clinical imaging studies that have shownthat serial Tc-99m sestamibi imaging is useful in assessingthe efficacy of coronary reperfusion in patients receiving thrombolytic therapy.“J2 The experimental studiessuggestthat in the presenceof acute infarction, Tc-99m sestamibiuptake during reperfusion reflects both the degree of reflow and the extent of viable myocardium. Hence, its properties are not simply akin to inert microspheresthat merely measure regional myocardial blood flow after reperfusion.
hours of coronary occlusion in a canine model. The planar REFERENCES defect size, but not the tomographic defect size, overesti- 1. Okada RD, Glover D, Gaffney T, Williams S. Myocardial kinetics of techneCirculation mated the pathologic size. After 48 hours of reperfusion, tium-99m-hexakis-2-methoxv-2-methvluroov~-isonitri~e. 1988;77:491-498. scintigraphic defect size was markedly reduced. Uptake 2. Canby RC, Silber S, Pohost GM. Relations of the myocardial imaging agents of Tc-99m sestamibi in ischemic myocardium increased g9’“Tc-MIBI and *O’TI to myocardial blood flow in a canine model of myocardial ischemic insult. Circulation 1990;81:289-296. significantly and correlated with the increase in regional 3. Li Q-S, Frank TL, Franceschi D, Wagner HN Jr, Becker LC. Technetiumflow as assessedby microspheres.Figure 6 comparesthe 99m methoxyisobutyl isonitrile (RP30) for quantification of myocardial ischemia reperfusion in dogs. J Nucl Med 1988;29:1539-1548. planar scintigraphic defect size during occlusion and re- 4.andVerani MS, Jeroudi MO, Mahmarian JJ, Boyce TM, Barges-Neto S, Pate1 perfusion with the pathologic infarct size in 12 dogs in B, Bolli R. Quantification of myocardial infarction during coronary occlusion and myocardial salvage after reperfusion using cardiac imaging with technetiumthis study. hexakis 2.methoxyisobutyl isonitrile. J Am Co11 Car-dial 1988;12:1573More recently, we have defined in our laboratory the 99m 1581. myocardial distribution of Tc-99m sestamibi before and 5. Sinusas AJ, Watson DD, Cannon JM Jr, Belier GA. Effect of ischemia and dysfunction on myocardial aptake of technetium-99m-labeled after coronary reperfusion in open-chest anesthetized postischemic methoxyisobutyl isonitrile and thallium-201. J Am Coil Cardiol 1989;14:1785dogs that underwent 3 hours of left anterior descending 1793. occlusion followed by 3 hours of reflow. lo When intrave- 6. Glover DK, Okada RD. Myocardial kinetics of Tc-MIBI in canine myocardiafter dipyridamole. Circulation 1990;8 1:628&636. nous Tc-99m sestamibi was administered during occlu- 7.urnLeppo JA, Meerdink DJ. Comparison of the myocardial uptake of a technesion only, the risk area defined by autoradiography corre- tium-labeled isonitrile analogue and thallium. Circ Res 1989;65:632-639. lated (r = 0.94) with the postmortem risk area, although 8. Meerdink DJ, Leppo JA. Comparison of hypoxia and ouabain effects on the uptake kinetics of technetium99m hexakis 2-methoxy-isobutyl isoniit was somewhat smaller. This was thought to be due to myocardial trile and thallium-201. J Nucl Med 1989;30:1500-1506. the presenceof collateral flow in vivo, which would not 9. Maublant JC, Gachon P, Moins N. Hexakis (2-methoxy isobutylisonitrile) influence the postmortem risk area. In dogs receiving Tc- technetium-99m and thallium-201 chloride: uptake and release in cultured myocardial cells. J Nucl Med 1988;29:48%54. 99m sestamibi 90 minutes after coronary reperfusion that 10. Sinusas AJ, Trautman KA, Bergin JD, Watson DD, Ruiz M, Smith WH, was precededby 3 hours of occlusion, To99m sestamibi Belier GA. Quantification of “area at risk” during coronary occlusion and degree myocardial salvage after reperfusion with technetium99m methoxyisobutyl activity was less than reperfusion flow. The defect area ofisonitrile. Circulation in press. defined by Tc-99m sestamibi autoradiography correlated 11. Wackers FJTh, Gibbons RJ, Verani MS, Kayden DS, Pellikka PA, Behrenclosely with the postmortem infarct size (r = 0.98) in beck T, Mahmarian JJ, Zaret BL. Serial quantitative planar technetium-99m imaging in acute myocardial infarction: efficacy for noninvasive assessthese reperfused dogs, as assessedby the dual simulta- isonitrile ment of thrombolytic therapy. J Am Co/l Car&l 1989;14:861&873. neousperfusion of monastral blue into the left main coro- 12. Gibbons RJ, Verani MS, Behrenbeck T, Pellikka PA, O’Connor MK, Mahnary artery and triphenyltetrazolium chloride into the marian JJ, Chesebro JH, Wackers FJ. Feasibility of tomographic 99mTc-hexakis2-methoxy-2-methylpropyl-isonitrile imaging for the assessment of myocardial left anterior descendingartery distal to the occlusion un- area at risk and the effect of treatment in acute myocardial infarction. Circulation 1989;80:1277-1286. der physiologic pressures. I.
SE
THE AMERICAN JOURNAL OF CARDIOLOGY
VOLUME 66
.I