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Cardiac myosin light chain-1 release in acute myocardial infarction is associated with scintigraphic estimates of myocardial scar
ELSEVIER
Clinica
Chimica
Acta 229 (1994) 153-159
Short communication
Cardiac myosin light chain-l release in acute myocardial infarction is associated with scintigraphic estimates of myocardial scar Johannes Mair*“, Ina Wagnera, Leo Fridrichb, Peter Lechleitner’, Franz Dienstlc, Bernd Puschendorf”, Gerd Micheld “Deparfmenf of Medical Chemistry and Biochemistry, bDeparfmenf ofNuclear Medicine, CDeparfment of Infernal Medicine, Universify of Innsbruck Medical School. Fritz-Preglsfrasse 3. A-6020 Innsbruck, Austria dAbboft European Research and Development, D-65205 Wiesbuden-Delke~heim~ German>
Received 2 February 1994; revision received 25 April 1994; accepted 5 May 1994
Keywords: Acute myocardial infarction; Cardiac myosin light chain-l; Creatine kinase-MB; Infarct size; Technetium-99m-isonitrile; Single photon emission computed tomography (SPECT)
To validate the effectiveness for acute myocardial infarction
and clinical
relevance
of therapeutic
interventions
(AMI) it is desirable to find simple and reliable methods to quantify infarct size. Previous experimental and clinical studies showed that reperfusion of the infarct-related coronary artery alters the release kinetics of cytoplasmatic proteins in AM1 and results in greater recovery of creatine kinase-MB (CKMB) per unit of infarcted myocardium [l]. Therefore, the accuracy of CKMB to quantify infarct size may be hampered by the administration of thrombolytic therapy. However, CKMB is only one among many other proteins which leak from damaged myocardium. Cardiac myosin light chains-l (cMLC-1) are contractile pro* Corresponding author. 0009~8981/94/$07.00 0 1994 Elsevier Science B.V. All rights reserved SSDI 0009-8981~94)05g8l-R
154
J. Muir et al. /Clin.
Chim. Acta 229 (1994)
153-159
teins and constituents of the myosin molecules which form the thick filaments of muscle libres. In experimental animals MLC release correlated closely with the histological infarct size [2]. In contrast to CKMB, the release of cMLC-1 is not significantly influenced by the occurrence of early reperfusion of the infarct-related artery [3,4]. In patients receiving thrombolytic treatment, cMLC-1 may be superior to CKMB to assess infarct size non-invasively. Thus, the purpose of the present study was to compare cMLC-1 and CKMB release with scintigraphic estimates of myocardial scar in AMI patients receiving thrombolytic treatment. 2. Materials and methods Of 25 consecutive, prospectively enrolled patients with first-time AMI, 17 patients (16 men, 1 woman; age: 54 f 8.7 years) gave informed consent for extra blood samples to be drawn and to myocardial scintigraphy. A cardiologist verified AM1 in all patients using the standard World Health Organization criteria. Three patients sustained an anterior and 14 an inferior wall AMI. On admission all patients showed ST segment elevation 20.1 mV in at least 2 contiguous leads in the same vascular territory. Subsequently, new persistent Q waves or equivalents developed in all but 3 patients. All patients took part in the International Study of Infarct Survival III and received intravenous thrombolytic therapy. They were randomized to either streptokinase, recombinant tissue-type plasminogen activator or anisoylatedplasminogen-streptokinase-activator-complex. Thrombolytic treatment was initiated 5 h (mean, range 0.5-16.5 h) after the onset of chest pain. On average, patients were discharged from hospital 12.5 days (range 6-19) after AMI. Acute coronary angiography was not performed in the patients investigated. However, in 12 patients (71%) rapid peaking of CK and CKMB (within 12 h and 10 h after the administration of thrombolytic treatment, respectively) indicated early reperfusion of the infarct-related coronary artery [5,6]. All patients had an uncomplicated AM1 and an uncomplicated course (no reinfarction or unstable angina pectoris) until myocardial scintigraphy. Blood samples were collected in ethylenediaminetetraacetic acidcoated tubes before the patients started therapy in the coronary care unit, every 4 h during the first 24 h after admission to the hospital, in 8-h intervals for the subsequent 24 h and then daily until the patient’s discharge. Plasma samples for measurement of CKMB and cMLC-1 were stored at -20°C until analysis. CK activities were measured without delay by a test kit of Merck (Darmstadt, Germany) and CKMB concentrations by a microparticle enzyme immunoassay (Abbott, Abbott Park, Illinois, USA). cMLC-1 were measured by a fully automated prototype assay for the Abbott IMx TM immunoassay system [7]. The limit of detection of the assay was 0.84 &l. No cMLC-I was measured in the samples of 79 healthy volunteers (50 men, 29 women, age 38 f 15 years and 39 + 19 years, respectively). Assay cross-reactivity with skeletal MLC-1 was 7.5%; there was no cross-reactivity with other cardiac or skeletal muscle proteins. Peak values and areas under concentration curves (AUC) of individual CKMB and cMLC-1 time courses were calculated as estimates of myocardial marker protein release after AMI. A value was defined as a peak if it was the highest in the concen-
J. Mair
et al. /Clin.
Chim.
Acta 229 (1994)
155
153-159
tration time course and if we observed at least one lower value before and after a maximal level. On average 5 weeks (range: 3-9) after the onset of AMI, scintigraphic estimation of infarct size was performed at rest under the effects of maximal anti-angina1 drug therapy by single photon emission computed tomography (SPECT) with technetium99m-isonitrile (Tc-sestamibi). One hour after the intravenous administration of 555 MBq Tc-sestamibi (Cardiolite, DuPont, Wilmington, DE, USA), each patient was given a small fatty meal to facilitate hepatobiliary excretion and to eliminate the imaging of gallbladder activity. One hour thereafter SPECT imaging was begun with a rotating LFOV gamma camera (Siemens ZLC370 equipped with a low-energy, allpurpose collimator; Siemens Medical, Iselin, NJ, USA). The entire 360” resolution was used to accumulate 64 projects with an acquisition matrix of 64 x 64 and an acquisition time of 20 s. Filtered backprojection was performed by use of Butterworth filter fifth order and a cut-off frequency of 0.5 (Nyquist). Data processing included alignment to the long axis of the left ventricle, rearrangement of data into short and long-axis slices, circumferential profiles, data compression into polar coordinates (‘bullseye’ polar coordinate maps) and comparison with pooled circumferential count values of a Tc-sestamibi specific normal database (modified Cedars-Sinai Hospital’s (Los Angeles, CA, USA) thallium-201 SPECT software [8]). Scintigraphic perfusion defect sizes were calculated as percentage of left ventricle and
14-
v -
T
12-
-400
cMLC-1 CKMB
- 350 - 300
lo-
- 250
4-
+J T
- 150
?? 5
- 100
20;
-200
-50 r
I
0
I
I
r
I
8
i
I
I
I
T
I
T
I
T
!()
12 24 36 48 60 72 84 96 108 120 132 144 156168 hours after admission
Fig. I. Cardiac myosin light chain-l (cMLC-1) and CKMB mass release in acute myocardial infarction. Data given as mean f standard error of the mean. On day 7 (168 h) cMLC-I and CKMB concentrations were only available in 16 patients.
156
J. Mair et al. /Clin.
Chim. Acra 229 (1994)
153-159
ranged from 3.2 to 47.8% (23.3 f 14%). Perfusion defects at rest on late images were assumed to reflect the relative sizes of myocardial scar [9]. Data are given as mean f S.D. unless otherwise stated. Linear (Pearson) correlation coefficients were calculated to describe the association between two variables.
lOOOOO-
y = - 2214.3 + 1096,7x
.
r=0.59
.
p = 0.013
8oooo_
0
60000-
0
10
20
Tc-sestamibi 20000-
.
1800016000-
30
40
SPECT defect size (%)
y = 2630.6 + 146,74x r = 0.46
p = 0.066 0
14000-
0 0
12000100008000-
2000-
.
0
0
0 01 0
0 10
20
Tc-sestamibi
30
I 40
1 50
SPECT defect size
Fig. 2. Correlation between cMLC-1 (A) and CKMB mass release (B) with scintigraphic estimates of myocardial scar. Patients with clinical evidence of early reperfusion of the infarct related artery are shown as open circles (0). patients without as solid points (0).
J. Mair et al. /C&I. Chim. Acta 229 (1994)
153-159
157
Student t-test was used for between-group comparison. P < 0.05 was considered to indicate statistical significance. 3. Results The CKMB and cMLC-1 time courses of the 17 patients investigated are summarized in Fig. 1. cMLC-1 increased 11.3 f 7.4 h (range 2-29 h) after the onset of symptoms and peaked at 94 f 51.4 h (range 32-230 h). A plateau was often observed around day 4 after admission (see Fig. 1). cMLC-1 peak concentration and cMLC-1 AUC correlated very closely (r = 0.92, P = 0.0001). cMLC-1 concentrations 3, 4, 5, 6, and 7 days after admission correlated closely with cMLC-1 AUC as well (0.73 < r c 0.89; P I 0.015). Time to peak values did not differ significantly (P= 0.15) between patients with and without evidence of early reperfusion of the infarct-related coronary artery. In all but 4 patients cMLC-1 was still increased at discharge. CKMB mass AUC did not correlate significantly with cMLC-1 AUC (r = 0.39, P = 0.121) and with scintigraphic defect sizes (r = 0.46, P = 0.066). By contrast, cMLC-1 AUC (r = 0.59, P = 0.013) and cMLC-1 peak values (r = 0.55, P = 0.022) were correlated with scintigraphic estimates of myocardial scar (see Fig. 2). In addition, cMLC-1 concentrations on day 6 after admission correlated closely both with Tc-sestamibi defect sizes (r = 0.66, P = 0.019) and with cMLC-1 AUC (r = 0.89, P = 0.0001) as well. In the subset of patients with early peaking of CK and CKMB (n = 12) the correlation between CKMB AUC and Tc-sestamibi infarct size was not stronger (r = 0.43, P = 0.16), whereas cMLC-1 AUC correlated significantly with scintigraphic estimates of myocardial scar in this subset as well (r = 0.62, P = 0.03). 4. Discussion The extent of the Tc-sestamibi defect on late images reflects final infarct size [9]. Tc-sestamibi myocardial uptake is directly related to myocardial blood flow. However, it is not only a perfusion agent. Its uptake is also dependent on the viability of myocytes [lO,ll]. When the flow is adequate, Tc-sestamibi myocardial uptake is dependent on sarcolemrnal membrane integrity and, to a lesser extent, intact mitochondrial function [9]. Animal studies have already shown a very close correlation (r = 0.95) between pathologic infarct size and both autoradiographic and SPECT Tc-sestamibi defect sizes [9,12,13]. Our patients were studied at rest at least 3 weeks after the onset of infarction and received maximal anti-angina1 therapy to optimize myocardial blood flow in regions supplied by patent vessels. This technique can be assumed to measure the final myocardial scar [9]. The calculation of defect sizes was confined to the left ventricle. Nevertheless, the correlation between scintigraphic estimates of infarct size and cMLC-1 release was close despite the large number of small and inferior infarctions in which scintigraphic methods for assessment of infarct extension are less accurate and far more problematic than in more extended anterior wall infarctions [14,15] and in which the right ventricle may contribute to myocardial protein release. The correlation between cMLC-1 release and scinti-
158
J. Mair el al. /C&I. Chim. Acta 229 (1994)
153-159
graphic estimates of infarct size is expected to be even closer in large or anterior wall infarctions. The fact that we cannot exclude - despite an uncomplicated course until myocardial scintigraphy in all patients - ‘silent’ reinfarctions with absolute certainty might also negatively influence correlations. In contrast to cMLC-.1, we did not find a significant correlation between Tc-sestamibi defect sizes and CKMB in our patients who all received thrombolytic treatment. This is most likely explained by the reperfusion dependent release of CKMB [l]. cMLC-1 release, on the contrary, is not significantly influenced by the occurrence of early reperfusion of the infarct-related artery [3,4]. Our results indicate that cMLC-1 is superior to CKMB in quantifying myocardial necrosis in patients receiving thrombolytic treatment, in particular when acute coronary angiographies are not performed and, therefore, patients cannot be classified into those with and without recanalization with absolute certainty. In clinical practice, the utility of cMLC-1 AUC may be limited by the necessity for protracted blood sampling. However, cMLC-1 peaks correlate closely with cMLC-1 AUC and daily blood sampling for 7 days seems to be sufficient to detect cMLC-1 peaks and to estimate cMLC-1 release. In addition, we often observed a plateau of cMLi=-1 concentrations around day 4 after admission and cMLC-1 concentrations on days 3-7 were closely correlated with AUC measurements. cMLC-I concentrations on day 6 after admission were also closely and significantly correlated with scintigraphic estimates of myocardial scar, and a single cMLC-1 measurement on day 6 might yield useful diagnostic information on infarct size, without the need for serial measurements. However, due to the dispersion of data observed, cMLC-1 determination can also be misleading in individua1 patients, particularly when comparing Tc-sestamibi defect sizes with cMLC-I results in patients with inferior wall myocardial infarctions. References [l] [2] [3]
[4]
[5]
[6]
[7] [8]
Roberts R, tshikawa Y. Enzymatic estimation of infarctsize during reperfusion. Circulation 1983;68(SuppL 1):1-83-I-89. Nagai R, Chiu CC, Yamaoki K et al. Evaluation of methods for estimating infarct size by myosin LC2: comparison with cardiac enzymes. Am J Physiol 1983;245:H413-H419. Katus HA, Diederich KW, Schwarz F, Uellner M, Scheffold T, Kuebler W. Influence of reperfusion on serum concentrations of cytosolic creatine kinase and structural myosin light chains in acute myocardial infarction. Am J Cardiol 1987:60:#0-~5. Isobe M, Nagai R, Ueda S et al. Quantitative relationship between left ventricular function and serum cardiac myosin light chain I levels after coronary reperfusion in patients with acute myocardial infarction. Circulation 1987;76:1251-1261. Gore JM, Roberts R, Ball SP. Montero A, Goldberg RJ, Dalen JE. Peak creatine kinase as a measure of effectiveness of thrombolytic therapy in acute myocardial infarction. Am J Cardiol 1987;59: 1234-1238. Zabel M, Hohnloser SH, Kiister W, Prim M, Kasper W, Just HJ. Analysis of creatine k&se, CKMB, myoglobin, and troponin T time-activity curves for early assessment of coronary artery reperfusion after intravenous thrombolysis. Circulation 1993;87: I542- 1550. Michel G, Seifert B, Ritter A. Automated microparticle capture immunoassay for the measurement of human cardiac myosin light chain-l. Clin Chem 1992;38: I 104. Clausen M, Henze E, Schmidt A et al. The contraction fraction (CF) in myocardial studies with technetium-99m-isonitril (MIBI) - correlations with radionuclide ventriculography and infarct size measured by SPECT. Eur J Nucl Med 1989;15:66-664.
J. Mair
[9]
et al. / Clin.
Chim.
Acta 229 (1994)
Christian TF, Schwartz RS, Gibbons RJ. Determinants acute myocardial infarction. Circulation 1992;86:8 l-90.
153-159
of infarct
size in reperfusion
159
therapy
for
[IO] Sinusas AJ. Trautman KA, Bergin JD et al. Quantification of area at risk during coronary occlusion and degree of myocardial salvage after reperfusion with technetium-99m methoxyisobutyl isonitrile. Circulation 1990;82: 1424-1437. [I I] Beller GA, Sinusas AJ. Experimental studies of the physiologic properties of technetium-99m isonitriles. Am J Cardiol 1990;66:5E-8E. [I21 Verani MS, Jeroudi MO, Mahmarian JJ et al. Quantification of myocardial infarction during coronary occlusion and myocardial salvage after reperfusion using cardiac imaging with technetium99m hexakis 2-methoxyisobutyl isonitrile. J Am Coll Cardiol 1988; 12: I573- I58 I. [I31 Maddahi J, Kiat H, Van Train KF et al. Myocardial perfusion imaging with technetium-99m sestamibi SPECT in the evaluation of coronary artery disease. Am J Cardiol 1990;66:55E-62E. [I41 Tamaki S, Nakajima H, Murakami T et al. Estimation of infarct size by myocardial computed tomography with thallium-201 and its relation to creatine kinase-MB release after myocardial infarction in man. Circulation 1982;66:994-1001. 1151 Strauss BH. Sobel BE, Roberts R. The influence of occult right ventricular infarction on enzymatically estimated infarct size, hemodynamics and prognosis, Circulation 1980:62:503-508.
Clinica
Chimica
Acta 229 (1994) 153-159
Short communication
Cardiac myosin light chain-l release in acute myocardial infarction is associated with scintigraphic estimates of myocardial scar Johannes Mair*“, Ina Wagnera, Leo Fridrichb, Peter Lechleitner’, Franz Dienstlc, Bernd Puschendorf”, Gerd Micheld “Deparfmenf of Medical Chemistry and Biochemistry, bDeparfmenf ofNuclear Medicine, CDeparfment of Infernal Medicine, Universify of Innsbruck Medical School. Fritz-Preglsfrasse 3. A-6020 Innsbruck, Austria dAbboft European Research and Development, D-65205 Wiesbuden-Delke~heim~ German>
Received 2 February 1994; revision received 25 April 1994; accepted 5 May 1994
Keywords: Acute myocardial infarction; Cardiac myosin light chain-l; Creatine kinase-MB; Infarct size; Technetium-99m-isonitrile; Single photon emission computed tomography (SPECT)
To validate the effectiveness for acute myocardial infarction
and clinical
relevance
of therapeutic
interventions
(AMI) it is desirable to find simple and reliable methods to quantify infarct size. Previous experimental and clinical studies showed that reperfusion of the infarct-related coronary artery alters the release kinetics of cytoplasmatic proteins in AM1 and results in greater recovery of creatine kinase-MB (CKMB) per unit of infarcted myocardium [l]. Therefore, the accuracy of CKMB to quantify infarct size may be hampered by the administration of thrombolytic therapy. However, CKMB is only one among many other proteins which leak from damaged myocardium. Cardiac myosin light chains-l (cMLC-1) are contractile pro* Corresponding author. 0009~8981/94/$07.00 0 1994 Elsevier Science B.V. All rights reserved SSDI 0009-8981~94)05g8l-R
154
J. Muir et al. /Clin.
Chim. Acta 229 (1994)
153-159
teins and constituents of the myosin molecules which form the thick filaments of muscle libres. In experimental animals MLC release correlated closely with the histological infarct size [2]. In contrast to CKMB, the release of cMLC-1 is not significantly influenced by the occurrence of early reperfusion of the infarct-related artery [3,4]. In patients receiving thrombolytic treatment, cMLC-1 may be superior to CKMB to assess infarct size non-invasively. Thus, the purpose of the present study was to compare cMLC-1 and CKMB release with scintigraphic estimates of myocardial scar in AMI patients receiving thrombolytic treatment. 2. Materials and methods Of 25 consecutive, prospectively enrolled patients with first-time AMI, 17 patients (16 men, 1 woman; age: 54 f 8.7 years) gave informed consent for extra blood samples to be drawn and to myocardial scintigraphy. A cardiologist verified AM1 in all patients using the standard World Health Organization criteria. Three patients sustained an anterior and 14 an inferior wall AMI. On admission all patients showed ST segment elevation 20.1 mV in at least 2 contiguous leads in the same vascular territory. Subsequently, new persistent Q waves or equivalents developed in all but 3 patients. All patients took part in the International Study of Infarct Survival III and received intravenous thrombolytic therapy. They were randomized to either streptokinase, recombinant tissue-type plasminogen activator or anisoylatedplasminogen-streptokinase-activator-complex. Thrombolytic treatment was initiated 5 h (mean, range 0.5-16.5 h) after the onset of chest pain. On average, patients were discharged from hospital 12.5 days (range 6-19) after AMI. Acute coronary angiography was not performed in the patients investigated. However, in 12 patients (71%) rapid peaking of CK and CKMB (within 12 h and 10 h after the administration of thrombolytic treatment, respectively) indicated early reperfusion of the infarct-related coronary artery [5,6]. All patients had an uncomplicated AM1 and an uncomplicated course (no reinfarction or unstable angina pectoris) until myocardial scintigraphy. Blood samples were collected in ethylenediaminetetraacetic acidcoated tubes before the patients started therapy in the coronary care unit, every 4 h during the first 24 h after admission to the hospital, in 8-h intervals for the subsequent 24 h and then daily until the patient’s discharge. Plasma samples for measurement of CKMB and cMLC-1 were stored at -20°C until analysis. CK activities were measured without delay by a test kit of Merck (Darmstadt, Germany) and CKMB concentrations by a microparticle enzyme immunoassay (Abbott, Abbott Park, Illinois, USA). cMLC-1 were measured by a fully automated prototype assay for the Abbott IMx TM immunoassay system [7]. The limit of detection of the assay was 0.84 &l. No cMLC-I was measured in the samples of 79 healthy volunteers (50 men, 29 women, age 38 f 15 years and 39 + 19 years, respectively). Assay cross-reactivity with skeletal MLC-1 was 7.5%; there was no cross-reactivity with other cardiac or skeletal muscle proteins. Peak values and areas under concentration curves (AUC) of individual CKMB and cMLC-1 time courses were calculated as estimates of myocardial marker protein release after AMI. A value was defined as a peak if it was the highest in the concen-
J. Mair
et al. /Clin.
Chim.
Acta 229 (1994)
155
153-159
tration time course and if we observed at least one lower value before and after a maximal level. On average 5 weeks (range: 3-9) after the onset of AMI, scintigraphic estimation of infarct size was performed at rest under the effects of maximal anti-angina1 drug therapy by single photon emission computed tomography (SPECT) with technetium99m-isonitrile (Tc-sestamibi). One hour after the intravenous administration of 555 MBq Tc-sestamibi (Cardiolite, DuPont, Wilmington, DE, USA), each patient was given a small fatty meal to facilitate hepatobiliary excretion and to eliminate the imaging of gallbladder activity. One hour thereafter SPECT imaging was begun with a rotating LFOV gamma camera (Siemens ZLC370 equipped with a low-energy, allpurpose collimator; Siemens Medical, Iselin, NJ, USA). The entire 360” resolution was used to accumulate 64 projects with an acquisition matrix of 64 x 64 and an acquisition time of 20 s. Filtered backprojection was performed by use of Butterworth filter fifth order and a cut-off frequency of 0.5 (Nyquist). Data processing included alignment to the long axis of the left ventricle, rearrangement of data into short and long-axis slices, circumferential profiles, data compression into polar coordinates (‘bullseye’ polar coordinate maps) and comparison with pooled circumferential count values of a Tc-sestamibi specific normal database (modified Cedars-Sinai Hospital’s (Los Angeles, CA, USA) thallium-201 SPECT software [8]). Scintigraphic perfusion defect sizes were calculated as percentage of left ventricle and
14-
v -
T
12-
-400
cMLC-1 CKMB
- 350 - 300
lo-
- 250
4-
+J T
- 150
?? 5
- 100
20;
-200
-50 r
I
0
I
I
r
I
8
i
I
I
I
T
I
T
I
T
!()
12 24 36 48 60 72 84 96 108 120 132 144 156168 hours after admission
Fig. I. Cardiac myosin light chain-l (cMLC-1) and CKMB mass release in acute myocardial infarction. Data given as mean f standard error of the mean. On day 7 (168 h) cMLC-I and CKMB concentrations were only available in 16 patients.
156
J. Mair et al. /Clin.
Chim. Acra 229 (1994)
153-159
ranged from 3.2 to 47.8% (23.3 f 14%). Perfusion defects at rest on late images were assumed to reflect the relative sizes of myocardial scar [9]. Data are given as mean f S.D. unless otherwise stated. Linear (Pearson) correlation coefficients were calculated to describe the association between two variables.
lOOOOO-
y = - 2214.3 + 1096,7x
.
r=0.59
.
p = 0.013
8oooo_
0
60000-
0
10
20
Tc-sestamibi 20000-
.
1800016000-
30
40
SPECT defect size (%)
y = 2630.6 + 146,74x r = 0.46
p = 0.066 0
14000-
0 0
12000100008000-
2000-
.
0
0
0 01 0
0 10
20
Tc-sestamibi
30
I 40
1 50
SPECT defect size
Fig. 2. Correlation between cMLC-1 (A) and CKMB mass release (B) with scintigraphic estimates of myocardial scar. Patients with clinical evidence of early reperfusion of the infarct related artery are shown as open circles (0). patients without as solid points (0).
J. Mair et al. /C&I. Chim. Acta 229 (1994)
153-159
157
Student t-test was used for between-group comparison. P < 0.05 was considered to indicate statistical significance. 3. Results The CKMB and cMLC-1 time courses of the 17 patients investigated are summarized in Fig. 1. cMLC-1 increased 11.3 f 7.4 h (range 2-29 h) after the onset of symptoms and peaked at 94 f 51.4 h (range 32-230 h). A plateau was often observed around day 4 after admission (see Fig. 1). cMLC-1 peak concentration and cMLC-1 AUC correlated very closely (r = 0.92, P = 0.0001). cMLC-1 concentrations 3, 4, 5, 6, and 7 days after admission correlated closely with cMLC-1 AUC as well (0.73 < r c 0.89; P I 0.015). Time to peak values did not differ significantly (P= 0.15) between patients with and without evidence of early reperfusion of the infarct-related coronary artery. In all but 4 patients cMLC-1 was still increased at discharge. CKMB mass AUC did not correlate significantly with cMLC-1 AUC (r = 0.39, P = 0.121) and with scintigraphic defect sizes (r = 0.46, P = 0.066). By contrast, cMLC-1 AUC (r = 0.59, P = 0.013) and cMLC-1 peak values (r = 0.55, P = 0.022) were correlated with scintigraphic estimates of myocardial scar (see Fig. 2). In addition, cMLC-1 concentrations on day 6 after admission correlated closely both with Tc-sestamibi defect sizes (r = 0.66, P = 0.019) and with cMLC-1 AUC (r = 0.89, P = 0.0001) as well. In the subset of patients with early peaking of CK and CKMB (n = 12) the correlation between CKMB AUC and Tc-sestamibi infarct size was not stronger (r = 0.43, P = 0.16), whereas cMLC-1 AUC correlated significantly with scintigraphic estimates of myocardial scar in this subset as well (r = 0.62, P = 0.03). 4. Discussion The extent of the Tc-sestamibi defect on late images reflects final infarct size [9]. Tc-sestamibi myocardial uptake is directly related to myocardial blood flow. However, it is not only a perfusion agent. Its uptake is also dependent on the viability of myocytes [lO,ll]. When the flow is adequate, Tc-sestamibi myocardial uptake is dependent on sarcolemrnal membrane integrity and, to a lesser extent, intact mitochondrial function [9]. Animal studies have already shown a very close correlation (r = 0.95) between pathologic infarct size and both autoradiographic and SPECT Tc-sestamibi defect sizes [9,12,13]. Our patients were studied at rest at least 3 weeks after the onset of infarction and received maximal anti-angina1 therapy to optimize myocardial blood flow in regions supplied by patent vessels. This technique can be assumed to measure the final myocardial scar [9]. The calculation of defect sizes was confined to the left ventricle. Nevertheless, the correlation between scintigraphic estimates of infarct size and cMLC-1 release was close despite the large number of small and inferior infarctions in which scintigraphic methods for assessment of infarct extension are less accurate and far more problematic than in more extended anterior wall infarctions [14,15] and in which the right ventricle may contribute to myocardial protein release. The correlation between cMLC-1 release and scinti-
158
J. Mair el al. /C&I. Chim. Acta 229 (1994)
153-159
graphic estimates of infarct size is expected to be even closer in large or anterior wall infarctions. The fact that we cannot exclude - despite an uncomplicated course until myocardial scintigraphy in all patients - ‘silent’ reinfarctions with absolute certainty might also negatively influence correlations. In contrast to cMLC-.1, we did not find a significant correlation between Tc-sestamibi defect sizes and CKMB in our patients who all received thrombolytic treatment. This is most likely explained by the reperfusion dependent release of CKMB [l]. cMLC-1 release, on the contrary, is not significantly influenced by the occurrence of early reperfusion of the infarct-related artery [3,4]. Our results indicate that cMLC-1 is superior to CKMB in quantifying myocardial necrosis in patients receiving thrombolytic treatment, in particular when acute coronary angiographies are not performed and, therefore, patients cannot be classified into those with and without recanalization with absolute certainty. In clinical practice, the utility of cMLC-1 AUC may be limited by the necessity for protracted blood sampling. However, cMLC-1 peaks correlate closely with cMLC-1 AUC and daily blood sampling for 7 days seems to be sufficient to detect cMLC-1 peaks and to estimate cMLC-1 release. In addition, we often observed a plateau of cMLi=-1 concentrations around day 4 after admission and cMLC-1 concentrations on days 3-7 were closely correlated with AUC measurements. cMLC-I concentrations on day 6 after admission were also closely and significantly correlated with scintigraphic estimates of myocardial scar, and a single cMLC-1 measurement on day 6 might yield useful diagnostic information on infarct size, without the need for serial measurements. However, due to the dispersion of data observed, cMLC-1 determination can also be misleading in individua1 patients, particularly when comparing Tc-sestamibi defect sizes with cMLC-I results in patients with inferior wall myocardial infarctions. References [l] [2] [3]
[4]
[5]
[6]
[7] [8]
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