clinical significance of early myocardial 99mtc-pyrophosphate uptake in patients with acute...

Okada and Boucher February 1987

American Heart Journal

artery reperfusion on myocardial infarct size and survival in conscious dogs. Circulation 1981;63:317-323.

22. Blanke H, Karsch KR, Schlueter G, Driesman M, Pichard A, Rentrop P. Preservation of R-waves after acute LAD-occlusion by streptokinase reperfusion [Abstract]. Circulation 1981;6‘i(SUppl Iv):g.

23. Reduto LA, Freund GC, Gaeta J, Killingworth B, Nussey G, Gould KL. Thallium redistribution following intracoronary streptokinase in acute myocardial infarction: relation to

changes in left ventricular performance [Abstract]. Circula- tion 1981;64(suppl IV):33.

24. Weinstein J, Sonnenblick EH, Cowley MJ, Lee G, Merx W, Mueller HS, Reduto LA, Rentrop P, Rutsch W. Improved left ventricular function and reduced hospital mortality following intracoronary thrombolysis in myocardial infarction with diminished ejection fraction [Abstract]. Am J Cardiol 1982;49:961.

Early *Tc-pyrophosphate (PYP) scintigrams of 29 patients receiving coronary thromboiysls lnduced by urokinase, 3.9 + 1.2 hours after the onset of acute myocar@ai infarction (AYI), were evaluated. intravenous -Tc-PYP scinttgraphy was performed 2.8 to &O-hours after the onset of AMI. AH 19 patients with positive findings on early rcintigrams had good recanaIization, compared to only 3 of the 10 patients wfth negattve findings. The seven patients with unsuccessful recanaiization after coronary thrombolysis had total occlusion or et&total occlusion with delayed washout of contrast material, and three of them had collaterals. The sensitivity, specificity, and predictive accuracy of positive results of early scintigraphy in predicting the presence of early reperfusion were 73%, lO@%, and 90%, respectively. PetMts with positive early scintigrams showed increasing regional ejection fractfon and decreasing thaiftum defect scores from the acute stage to the chronic stage. There findings indicate that eariy eR”Tc-PYP scintlgraphy is a sensitive noninvasive technique for detecting eariy recanalir;ation in infarcted vessels. The collateral flow or antegrade flow with delay Is not enough to cause *Tc-PYP uptake in a very earty stage of AMI. (AM HWU J 1987; 113~250.)

Makoto Kondo, M.D., Mamoru Takahashi, M.D., Tetauya Matauda, M.D., Noriaki Kume, M.D., Youske Yuzuki, M.D., Yukio Shimono, M.D., and

Hisayoshi Fujiwara, M.D. Shizuoka and Kyoto, Japan

Recently, reperfusion of acutely occluded coronary arteries by thrombolytic agents or by bypass graft- ing surgery has been used to limit the size of an acute myocardial infarction (AMI). However, some experimental and clinical studies have demon- strated the presence of contraction band necrosis and hemorrhagic infarction after reperfusion.1-5 99”Tc-pyrophosphate (PYP) as an infarct-avid agent is generally considered to be an indicator of myocardial necrosis occurring more than 12 hours after the

onset of AMI.6-10 A few recent experimentaW* and clinical studies15-17 revealed the early appearance of -Tc-PYP hot imagings after transient occlusions. However, little is known about early myocardial *Tc-PYP uptake related to the coronary anatomy in human AMI. Therefore, we compared the results of early %Tc-PYP scintigraphy and coronary arteriography in pat&& with AMI, who underwent coronary thrombo1ysia.

METHODS

From the Division of Cardiology, Shimada City Hospital, and the Third Study patients. The study group consisted of 29 Division, Department of Internal Medicine, Kyoto University. patienti (11 women and 18 men) with AMI, admitted to Received for publication Nov 7, 1985; accepted July 2, 1986. the coronary care unit at Shimada City Hospital. All Reprint requests: Makoto Kondo, M.D., Division of Cardiology, Shimada patients had chest pain, which persisted for mcrre than 30 City Hospital, 1200-5 Noda Shimada, Shizuoka 427, Japan. minutes and was unresponsive to nitroglycerin; ECGs

250

Volume 113

Number 2. Pert 1 Early 99mTc-PYP uptake in AMI 251

Table I. Characteristics of study population

Characteristics GFOU~ 1

No. of patients 19

Age W 61 f 12.1

Sex

Male 11 (58%)

Female 8 (42%) Unstable angina 8 (42%) Remote MI 5 (26%) Peak CK (NJ/L) 1348 + 583.0 Infarct-related vessel

LAD 14 (74%) RCA 4 (21%)

LC 1( 5%)

GFOU~ 2

10

64 k 10.5 NS

7 (70%) NS

3 (30%)

4 (40%) NS

0 (0%) p <O.l

1678 -+ 770.7 NS

4 (40%) NS

4 (40%)

2 (20%)

Group 1 = patients with successful recanalization; group 2 = patients with

unsuccessful recanalization; LAD = left anterior descending artery; LC = Left circumflex artery; RCA = right coronary artery; MI = myocardi-

al infarction: CK = creatine kinase.

showed evidence of ST segment elevation in at least two leads. Patients underwent emergency coronary arteriography 3.9 + 1.2 hours after the onset of AMI. All patients were diagnosed as having AM1 by serial enzyme analysis and ECG.

Radionuclide studies Imaging protocol. After coronary thrombolysis, all

patients received an intravenous injection of g”Tc-PYP (20 mCi) 5.6 + 1.2 hours (range 2.8 to 8.0) after the onset of AMI. *Tc-PYP scintigraphy was performed 2 hours after intravenous injection. In patients with negative findings, *“Tc-PYP scintigraphy was repeated 22 to 78 hours after the onset of AMI. Resting thallium-201 myocardial perfusion scintigraphy was performed within 3 days after the onset of AMI. Thallium-201 imaging was begun 10 minutes after intravenous injection (2 mCi). Thallium-201 scintigraphy was repeated between 12 and 19 days after the onset of AMI. Patients were imaged in anterior, 45degree left anterior oblique, and left lateral projections. All studies were performed by means of a Hitachi RC-IC-1635 LD scintillation camera equipped with a low-energy, high-resolution, parallel-hole col- limator.

Scintigraphic analysis. All images were analyzed visually without knowledge of the patient’s clinical data. 99mTc-PYP scintigrams were graded from 0 to 4+, as described by Willerson et al.“; positive scintigrams were those graded 2+ or greater. 99mTc-PYP scintigrams were also classified as to those showing focal or d&se uptake. For analysis of thallium-201 scintigrams, each image was divided into five roughly equal segments for a total 15 segments and examined by segmental analysis of thallium-201 imaging for location of coronary artery disease as described by Rigo et al. Ia The thallium uptake of each segment was classified as the thallium defect score from 0 to 2 (normal activity = 0, reduced activity = 1, absent activity = 2). To define whether the location of myocardial *Tc-PYP uptake corresponded with the ECG site of AMI, the 99mTc-PYP imaging and the thallium-201 imag-

Emergency Coronary Arteriography (l.S-6.1 hrs) 29

Spontaneous Recanalkation

4

Occlusion 25

Success Failure 16 7

I I I I . . . . . .

- - Mm-PYP I wnravenous mjectlon or IO -- --. I z.a---e.onrs(average 5.6hrs)

I ---- I Pay 1 INe9;tivel 1 Posii 1 INeg;tive]

Fig. 1. Results of coronary thrombolysis and intravenous 99mTc-PYP scintigraphy. See text for details. UK = urokinase.

ing were superimposed according to the dual-imaging approach.lg

Cardiac catheterization. By means of the percutaneous femoral Seldinger approach, single-plane left ventricular cineangiography was carried out in the 30-degree right anterior oblique projection after the intravenous injection of heparin (3000 U). Selective coronary arteriography of both left and right coronary systems was performed in several projections. If total occlusion or subtotal occlusion with delayed washout of contrast material was identified in the infarct-related vessel, after the sublingual absorp- tion of nitroglycerin, intracoronary infusion of urokinase (UK) was begun. Injection of contrast material was repeated every 10 minutes. The total dose of UK ranged from 720,000 to 1,680,OOO U. After the infusion of UK was stopped, left and right coronary arteriography was repeated. Left ventricular and coronary arteriography was repeated 4 weeks later.

Angiograms were interpreted independently by three experienced physicians and the ejection fraction (EF) was calculated. The regional EF of the infarcted area was determined by the area method described by Gerberg et al.*O The ventriculogram was separated into five areas. Myocardial regions that corresponded to the perfusion area of the infarct vessel were averaged (anterior myocardial infarction-anterobasal, anterolateral, and apical areas; inferior myocardial infarction-apical, diaphrag- matic, and posterobasal areas). In the present study, three patients had an occluded lesion in the left circumflex artery and two of the three patients had an evaluable left ventricular cineangiogram. In these two patients, a poste- rior descending artery branched from the left circumflex artery, end ECGs showed acute inferior myocardial infarction. Therefore, the regional EF was evaluated as the area of inferior myocardial infarction. The degree of stenosis in the coronary artery was expressed as the percentage of

252 Kondo et al. February 1987


Table II. Early *Tc-PYP scintigraphic and coronary arteriographic data in group 1

Patient No.

wmTc-PYP scan

Time to injection (hr) Grade

Infarct-related vessel

Coronary arteriography

Before UK After UK

1 7 4+ RCA 2 6 2+ LAD 3 6 3+ LAD 4 5.5 3+ LAD 5 5 2+ LAD 6 6 2+ RCA 7 6 3+ LAD 8 5 3+ LC 9 5.5 2+ LAD

10 5 3+ LAD 11 4.5 2+ LAD 12 4.8 2+ RCA 13 2.8 2+ LAD 14 5.9 2+ LAD 15 6.4 2+ RCA 16 4 2+ LAD 17 7 3+ LAD 18 3.1 2+ LAD 19 5 2+ LAD

100% collaterals (+) 90% 99% 100% collaterals (++) 99% D collaterals (++) 100% 99% D 99% 75% 100% collaterals (++) 100% collaterals (++) 99% D collaterals (++) 100% collaterals (+++) 99% D collaterals (++) 100% collaterals (+) 100% 99% D collaterals (++) 99% D 99% D collaterals (++)

-

90% 90% collaterals (++I 75% 99%

90% 50% 75% 75% 90% 99% 75% 50% 99% 90%

UK = urokinaee; D = delayed washout of contrast material; (+) = poor collaterals; (++) = intermediate collaterals; (+++) = good collaterals; - = not done; other abbreviations as in Table I.

reduction in diameter based on the American Heart Association report.2l Successful recanalization by coronary thrombolysis was defined as rapid antegrade fiIling of the distal portion of the previously occluded vessel. We considered a recanaliiation unsuccessful if delayed washout of the distal vessel was visualized, such that visualization was incomplete at a time when branches proximal to the sit8 of obstruction were completely filled with contrast materialz2 and the distal vessel was not completely filled within 7 seconds after intracoronary injection of contrast material. The extent of collaterals in pre- and postcoron- ary thrombolysis was graded visually on each coronary arteriogram: “good” if most or all of the vessels distal to the lesion were readily visualized; “intermediate” if a part of them distal to the lesion was visualized, or “poor” if only branches, but no distal filling of the infarcted vessel, were visualized.

StatistIcal analysis. Analysis of difference was performed by means of the chi-square test or unpaired t test. For comparison of acute and chronic stages, a paired t test was used for EF, regional EF, and thallium defect score. Results were expressed as the mean 2 standard deviation. A significant difference was considered present when a p value less than 0.05 was observed. The standard methodz3 was used for calculation of sensitivity, specificity, and predictive accuracy.

RESULTS

Fig. 1 shows the findings of initial coronary arteriography and coronary thrombolytic therapy in the 29 patients. Four patients showed good spontaneous

reperfusion. The other 25 patients had total occlusion or subtotal occlusion with delayed washout of contrast material at initial coronary arteriography. Eighteen of the 25 patients showed successful recanalization by intracoronary infusion of UK.

Patients were divided into two groups according to early 99mTc-PYP scintigraphic results: group 1 (n = 19) with positive scintigrams and group 2 (n = 10) with negative scintigrams. Table I shows the clinical and ark&graphic characteristics of the two groups. There was no significant difference in the frequency of the preceding unstable angina, peak creatine kinase activity, or location of the infarcted vessel between. the two groups. Although not significantly difkent, five patients in group 1 had a history of remote myocardial infarction. In three of them, the location of the AMI was difkent from that of the remote myocardial infarction.

Early oo”Tc-PYP [email protected] data. The interval from the onset of AMI until the injection of the tracer was signii (p < 0.95) shorter in group 1 (5.2 f 1.2 hours) than in group 2 (6.4 + 0.9 hours). Twelve patients in group 1 showed 2+ activity (Table II). In 7 of the 12 patients, BB”Te-PYP uptake was focally noted and the other fiv8 showed a diffuse pattern. SK of the aeven p&3& in group 1 showed 3+ and one showed 4+ activity (Table II).

All 19 patients in group 1 had good reperfusion

Volume 113

Number 2. Part 1 Early g9”Tc-PYP uptake in AMI 253

Fig. 2. Left coronary arteriogram and early 99mT~-PYP scintigram in a patient (No. 16) with successful recanalization. Complete occlusion of the proximal anterior descending coronary artery (arrow) before and immediately after successful thrombolysis (top). After thrombolysis, rapid filling of the distal anterior descending coronary artery was observed. *Tc-PYP scintigram performed 4 hours after the onset of AM1 showed positive (arrow) (bottom). ANT = anterior; LAO = left anterior oblique; UK = urokinase.

(Fig. Z), compared with only three patients in group 2 (Fig. 1, Tables II and III). The sensitivity, specificity, and predictive accuracy of the positive results of early -Tc-PYP scintigraphy in predicting the presence of early good reperfusion were 73 % ,100 % , and 90%, respectively. Good or intermediate collateral vascularixation was noted in the three patients with unsuccessful recanalization in group 2 after coronary thrombolysis (Table III). In 9 of the 10 patients in group 2, %Tc-PYP scintigraphy was repeated 22 to 78 hours after the onset of AM1 and became positive in six.

Adequate left ventricular cineangiography before coronary thrombolysis and after 4 weeks was obtained in 15 of the 19 patients in group 1. The regional EF of the infarcted area increased significantly (30 + 12.4% to 37 f 10.2%, p < O.Ol), although EF did not (52 rt 12.4% to 54 t- 10.6%). In 18 of the 19 patients in group 1, the resting thallium-201 scintigraphy was serially studied. The thallium defect score of the infarcted area decreased significantly from the acute stage (5 f 2.6) to the chronic stage (2 + 1.9; p < 0.01) (Fig. 3). In group 2, three of four patients with serial ventriculograms showed a decrease of EF and regional EF after the acute stage to the chronic stage. Two of six patients with serial thallium-201 scintigrams had unsuccess-

ful recanalization and no improvement in defect score. The other four patients, including three patients with successful recanalixation, showed improved thallium defect scores.

DISCUSSION

Clinical significance of early QmTc-PYP scintigraphy. Myocardial scintigraphy with &Tc-PYP is a valu- able method for detecting acute myocardial necro- sis6-lo %Tc-PYP scintigrams do not show positive findings for at least 12 hours after the onset of AML6v8 In a few experimental studies,“-” animals subjected to transient occlusion had positive %Tc- PYP scintigrams before the twelfth hour after occlusion of coronary arteries. Recently, Schafer et all6 reported that patients with streptokinase-induced reperfusion showed early accumulation with *Tc- PYP, and Wheelan et all7 found that patients with early peaking MB-CK after intravenous streptokinase infusion showed early positive %Tc-PYP scintigrams. However, few studies have compared the results of early -Tc-PYP scintigraphy and coronary anatomy in the acute stage. We found that 73% of the patients with early good reperfusion in the infarcted vessels showed positive scintigraphic flnd- ings 2.8 to 8.0 hours after the onset of AMI. In contrast, all patients with unsuccessful thrombolysis

254 Kondo et al. February 1987


EF(%)

80

m

60

n=l5

rNS1

30 1 .

. 20

10

1

14-t

13-

12-

11 -

10 -

9.

0-

7-

6-

s-

4-

3-

2-

l-

OAc:te kixT?z- r

Fig. 3. Serial changes of EF, regional EF, and thallium defect score from acute stage to chronic stage in group 1. See text for details. EF = ejection fraction; Tl = thallium.

T I Defet

n=l5

r P<O.Oll

Score

n=18

rP<O.Oll

Table III. Serial 99mTc-PYP scintigraphic and coronary arteriographic data in group 2

*Tc-PYP scan

Patient Time to No. injection (hr) Grade

20 6 0 22 2+

21 8 1+ 55 3+

22 6.8 1+ 57.7 2+

23 5 1+ 22.3 1+

24 7.3 0 25 5.5 1+

32 3+ 26 6 1+

22 2+ 27 6 1+

38 4+ 28 6.2 1+

77.8 1+ 29 7 0

60.5 0

Abbreviations as in Tables I and II.

Infarct-related vessel

LC

RCA

LAD

RCA

LAD LAD

LAD

RCA

RCA

LC

Coronary arteriography

Before UK After UK

100% collaterals 100% collaterals (++) (++) 100% collaterals 100% collaterals (++) (++) 99% D 99% D

100% collaterals 99% D collaterals (++) (++) 100% 100% 100% 100%

99% D 99% D

99% D collaterals 75%

(++I 100% collaterals 50% (++I 100% 90%

showed negative scintigraphic &dings. Therefore, infarcted area from the acute stage to the chronic an early positive BB”Tc-PYP scintigram is a good stage. In ad&ion, we found a significant increase of indicator of early reperfusion in the infarcted ves- regional EF in the infarcted area from the acute sels. stage to the chronic stage. Although we did not

Schafer et al.16 reported that patients with posi- obtain satisfactory data in group 2, Sheehan et aL2’ tive results of early %Tc-PYP scintigraphy had a reported that rxmrevaseulari~ patients w&h AM1 significantly decreased thallium defect size in the did not show improvement in regional EF in the

Volume 113

Number 2, Part 1

infarcted area from the acute stage to the chronic stage. These findings suggest that early positive 99mTc-PYP scintigrams may reflect salvage of the ischemic myocardium.

Mechanisms for myocardial OO”Tc-PYP uptake following reflow in AMI. Willerson et al6 suggested that some residual collateral coronary blood flows into the necrotic myocardium and that an adequate time lag between the onset of myocardial damage and the beginning of 99mTc-PYP myocardial scintigraphy is necessary for myocardial 99mTc-PYP uptake. Hol- man et all5 reported that myocardial 99mTc-PYP uptake occurs during the early stage of AM1 and speculated that the mechanism involves the trans- portation of the tracer by rapidly established collateral flow. However, they did not describe the detailed findings of the coronary anatomy in the acute stage. Our findings of total occlusion or subtotal occlusion with delayed washout of contrast material, regardless of the presence or absence of the coronary collaterals seen on coronary arteriography, were consistent with the negative results of early ggmTc-PYP scintigraphy. Rapidly recanalized antegrade flow without a delay was the predominant angiographic finding in patients with early myocardial %Tc-PYP uptake. This suggests that collateral flow or antegrade flow with delay is not enough to cause the gsmTc-PYP uptake in the very early stage of AMI.

Experimental studies7*g-12 have shown that the pathophysiologic basis for a positive 99mT~-PYP scintigram is calcium accumulation and tracer trans- portation into the damaged myocardial cells as a result of residual flow. In human and animal models, sudden restoration of large blood flow to the nonper- fused myocardium results in massive calcium over- load to the ischemic cells and causes contraction band necrosis immediately after reflow.‘-*’ I23 25* 26 This suggests that myocardial s9”Tc-PYP uptake at a very early stage of AM1 may directly reflect the reperfusion necrosis. Thus, we speculate that successful recanalization may follow both the salvage of the ischemic myocytes and acceleration of cell death, depending on the degree of ischemic damage of the myocardial cell membrane before reflow.

Clinical implication. The present study demon- strated that early myocardial wmTc-PYP uptake is closely related to the sudden restoration of coronary antegrade flow. This implies that *Tc-PYP scintigraphy is a reasonably sensitive noninvasive technique for detecting the presence of early good reperfusion by thrombolysis. While early %Tc-PYP scintigraphy immediately after coronary thrombolysis is a noninvasive indicator of early reperfusion, it

Early 99mTc-PYP uptake in AMI 255

does not indicate whether any residual viable myocardium remains. This greatly limits the clinical usefulness of the approach. Further comparative investigations among angiographic, s9”Tc-PYP scintigraphic, and pathologic examinations in many patients is needed.

We are grateful to the nurses in the second station of internal medicine for making this study possible. We thank Yoshihisa Mori, Kiyotaka Suzuki, and Shinji Fujioka for their technical assistance.

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