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Improved detection of minor ischemic myocardial injury with measurement of serum cardiac troponin I.

Currently, the biochemical diagnosis of acute myocardial infarction (AMI) (2) is confirmed by observing a serial rise and fall in the serum activity of creatine kinase (CK) and its MB isoenzyme (CK-MB) [1]. Although the use of these enzyme markers enjoys widespread acceptance, both CK and CK-MB have deficiencies. First, both CK and CK-MB are present in tissues other than the myocardium. A serial rise and fall of these enzymes can be observed with conditions other than AMI [2, 3]. Second, it is now recognized that profound ischemic cardiac injury can occur without myocardial necrosis and the release of CK and CK-MB can occur without infarction [4]. Confusion therefore exists with respect to the enzymatic diagnosis of AMI, especially when release of CK and CK-MB is minimal. The diagnostic problem in AMI with an increased CK-MB in the absence of abnormally increased total CK has challenged clinicians for decades [5]. As a result, the definition of an AMI varies widely among physicians, hospitals, and countries. Recently, two new markers have become available for detection of myocardial injury. Cardiac troponin I (cTnI) and cardiac troponin T (cTnT) offer improved specificity and sensitivity for detection of acute myocardial injury when compared with CK-MB in patients with suspected acute myocardial injury [3, 6, 7]. In this study, we prospectively compared serum cTnI with CK-MB mass measurements in patients with minor ischemic myocardial injury on the basis of minimal increases of total CK activity and electrocardiography or echocardiography findings.

Materials and Methods

This study was conducted at the Hennepin County Medical Center, a 450-bed teaching hospital that provides acute care for the city of Minneapolis, MN. Over an 8-month period we identified 48 consecutive patients with a diagnosis of acute minor ischemic myocardial injury. We defined minor ischemic myocardial injury as follows: (a) chest discomfort suggestive of acute myocardial ischemia, (b) peak total CK activity less than twice the upper reference limit (300 U/L for men; 200 U/L for women), and either (c) electrocardiogram (ECG) alterations indicative of ischemic injury or evolving AMI, defined as ST-segment deviations (ST-segment depression or elevation $0.1 mV on at least two contiguous leads) or new symmetric T-wave inversions [greater than or equal to]0.1 mV, or both, or (d) two-dimensional echocardiogram (echo) alterations indicative of a new or presumably new regional wall motion abnormality. All patients were assessed by detailed clinical examination during a 24-72-h period after admission. Patients were not included if they had a peak total CK activity >600 U/L or had fewer than two blood samples drawn. All the biochemical measurements vs time were based on onset of chest pain.

Serial ECGs were performed on admission and thereafter at least once daily for all patients. ECGs were evaluated by an experienced cardiologist who was unaware of the biochemical marker results. A two-dimensional echo was recommended but not required for all patients. Coronary arteriograms were obtained at the discretion of the attending clinician and were not a criterion for this study.

Clotted blood samples (serum) for analysis of CK-MB mass and cTnI were obtained at admission and every 6-8 h for 36 h. The concentration of CK-MB was measured on the Stratus II analyzer (Dade International) by a mass immunoassay on the basis of a monoclonal antibody that specifically recognizes CK-MB [8]. The lower limit for detection of CK-MB was 1.0 [micro]g/L. Imprecision (CV) was 4.8% at the upper reference limit of 5.0 [micro]g/L. cTnI also was measured on the Stratus II analyzer (Dade International) by a mass immunoassay that uses two monoclonal antibodies specific for independent epitopes of cTnI [9]. The lower limit for detection of cTnI was 0.35 [micro]g/L. Imprecision (CV) was 9.5% at the upper reference limit of 0.8 [micro]g/L. Total CK activity was measured at 37 [degrees]C on a Vitros analyzer with a kinetic enzymatic method (Johnson and Johnson Co.). The upper reference limits for total CK had been determined nonparametrically, stratified for men and women of mixed race, who were hospitalized without cardiac pathology. The biochemical marker index was defined as and calculated from the measured serum marker concentration divided by the upper reference limit (i.e., CK-MB concentration/5.0; cTnI concentration/0.8).

Statistical comparisons of cTnI and CK-MB data were analyzed by one-way and two-way analyses of variance. Results are reported as mean [+ or -] 95% confidence intervals (bars on graphs) and SD. The level of significance was set at 0.05.


Between October 1995 and May 1996 we identified 48 consecutive patients with a diagnosis of acute minor ischemic myocardial injury, 27 (54%) men and 21 (46%) women (Table 1). The mean age was 65 years (range 33-96 years). The mean KILLIP class was 1.3 (range 1-3). Electrocardiographic evidence of myocardial ischemia was present in 39 (81%) of the 48 patients. The ischemic change was ST-segment depression in 13 patients, ST-segment elevation in 17 patients, T-wave inversion in 13 patients, and combined T-wave inversion and ST-segment deviation in 6 patients. New Q-waves evolved in 5 patients. A two-dimensional echo was performed in 43 (90%) of the patients. In 32 patients the echo revealed a presumed new regional wall motion abnormality. This involved the anterior wall (n = 16), the inferior wall (n = 14), or the posterior wall (n = 2). In = patients no echo was performed because of previously known ischemic cardiomyopathy; however, all showed evidence of ischemic injury by ECG. Coronary arteriograms were obtained in 30 of the 48 patients (62.5%). Twenty-seven of the 30 (90%) arteriograms demonstrated 90-100% occlusion in at least one coronary artery, indicating that coronary artery disease was present. Eighteen of these were in patients whose total CK peaked within the reference range. Arteries in the other three patients demonstrated 20%, 40%, and 70% occlusions by angiography.

A summary of biochemical findings together with ECG and echo findings for all patients is presented in Table 1. The peak CK activity was within normal limits in 28 (58%) patients. The mean ([+ or -]SD) peak CK was 282 [+ or -] 144 U/L (range 55-584 U/L). The mean peak CK-MB was 16.4 [+ or -] 11.8 [micro]g/L (1.2-52.5 [micro]g/L). The mean peak cTnI was 13.2 [+ or -] 13.0 [micro]g/L (0.4-47.7 [micro]g/L). The peak cTnI concentrations correlated significantly with the peak CK-MB concentration (P <0.0001; r 5 0.58) and peak total CK activity (P = 0.002; r 5 0.45). As shown in Fig. 1, within each biochemical marker index group, cTnI was significantly increased (P <0.01) at all time periods compared with the values at 0-6 h, whereas CK-MB was increased significantly only at 7-12 h (P <0.01) and 13-18 h (P <0.05) compared with the values at 0-6 h. Between groups, the cTnI index was increased significantly (P <0.05- 0.001) compared with CK-MB from 7 to 36 h after the onset of chest pain (Fig. 1). The clinical sensitivities (defined as the number of patients with increased activity above the upper reference limit compared with all 48 patients) with 95% confidence intervals of cTnI and CK-MB at each time period following onset of chest pain are shown in Table 2. Neither marker was a good early indicator of myocardial injury at <6 h (sensitivities <40%); however, the sensitivity of cTnI at 7-36 h after the onset of chest pain was 88-100%, a substantial improvement over CK-MB (sensitivity 61-81%).


During the past two decades, several studies have described the entity called microinfarction or non-Q-wave infarction, characterized by an increased CK-MB in the presence of normal total CK [5]. Retrospective review of these studies reveals frequent clinical indicators of infarction (documented by ECG and echo) with the above enzyme pattern occurring more commonly in older patients. Further, because the ECG is nondiagnostic in 50% of patients with AMI, the confirmation of the diagnosis often requires the quantitative detection of CK-MB [1]. Our study presents unique data regarding the sensitive detection of minor ischemic myocardial injury with the use of serial measurements of cTnI in 48 consecutive patients with minimal increase of total CK activity within 36 h after the onset of chest pain. Determinations of both cTnI and CK-MB mass within several time frames over 36 h after onset of chest pain demonstrated cTnI to have higher clinical sensitivity (100%) than CK-MB mass did (82%) (Table 2). Further, within each time frame after 6 h, the cTnI index was significantly increased compared with CK-MB (Fig. 1). Thus, our data suggest that detection of myocardial injury during the course of minor ischemic injury may be facilitated by the measurement of serum cTnI.


The definition of an AMI on the basis of enzyme criteria (total CK and CK-MB) varies widely, both in the US and internationally. Many investigators have required the total CK activity to exceed twice normal before establishing the diagnosis of an AMI [10]. In our study of patients that display clinical evidence for myocardial injury (Table 1), an increased total CK activity less than twice the upper limit of the reference interval accounted for 42% of the study population, with the other 58% having normal total CK activities. Further, the cardiac catheterization findings documented that substantial coronary artery disease was present in our patient study group, with 18 patients with peak total CK activities less than the upper reference limit demonstrating >90% coronary artery occlusion of at least one vessel.

Minor increases of cTnI or CK-MB can serve as markers for the occurrence of an episode of severe myocardial ischemia, regardless of whether they are indicative of reversible or irreversible injury [11-13]. Further, patients with minor ischemic myocardial injury who demonstrate a release of either CK-MB or cTnI are at increased risk for future MI and death. Thus, increases in biochemical markers may lead clinicians to certain types of treatment. A recent study examined the prognostic value of cTnI activity in patients with unstable angina or non-Q-wave MI [14]. The mortality rate at 42 days was significantly higher in the patients with measurable cTnI ([greater than or equal to]0.4 [micro]g/L) than in those with undetectable amounts (<0.4 [micro]g/L), thus providing useful prognostic information and permitting early identification of patients with an increased risk of death. Although the current study was limited because no patient follow-up data were obtained, our findings complemented the study of Antman et al. [14]. cTnI measurements have also been used for risk stratification of non-AMI patients admitted with chest pain [15]. With the use of odds ratios, Wu et al. [15] showed that poor outcomes were significantly more frequent in the increased serum cTnI group than in the normal serum cTnI group, a substantial improvement over CK-MB implications. Further, preliminary evidence has shown that increased serum cTnI could be used for screening and risk assessment in congestive heart failure patients [16].

Our findings complement other studies that have demonstrated cTnI to be a very sensitive marker for AMI in patients admitted to intensive care units with a high probability of AMI, although we show cTnI not to be a sensitive early marker (Table 2) [17, 18]. The very low to undetectable cTnI values in serum from noncardiac diseased and apparently healthy patients permits use of very low discrimination values compared with higher values of CK-MB for the determination of myocardial injury. Despite the possibility that there may be other tissue sources of cTnI not yet understood, the apparent unique aspect of cTnI as being 100% tissue-specific for the myocardium [9] makes it an excellent marker to serve as a biochemical tool for detecting myocardial injury in serum as well as differentiating patients that often show falsely increased CK-MB concentrations. These include patients with chest trauma [19], cocaine-associated chest pain [20], criticalness in ill intensive care [21], muscle trauma and disease [3], and renal disease [22]. Increased cTnI amounts in patients with little or no clinical evidence suggestive of myocardial injury should alert the clinician to consider occult cardiac injury or disease. One limitation of the study design was that our population had a higher incidence of ischemic heart disease (as defined by ECG and echo findings and documented by angiography findings) and that our findings may not be easily extrapolated to larger patient populations. Another potential limitation of this study was its relatively small sample size; however, our data add to growing literature supporting cTnI as the preferred marker compared with CK-MB for the detection of minor ischemic cardiac injury. These findings further demonstrate the need to reevaluate the use of a twofold increase of total CK activity as a criterion for AMI.

This work was supported in part from a grant from Dade International, Inc.

Received April 16, 1997; revision accepted July 25, 1997.


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[4.] Piper HM, Schwartz P, Spahr R, Hutter JF, Speickermann PG. Early enzyme release from myocardial cells is not due to irreversible cell damage. J Mol Cell Cardiol 1984;16:385-8.

[5.] Lipsitz LA, Pluchino FC, Wei JY. The prevalence and prognosis of minimally elevated creatine kinase myocardial band activity in elder patients with syncope. Arch Intern Med 1987;147:1321-3.

[6.] Wu AHB, Feng YJ, Contois JH, Pervaiz S. Comparison of myoglobin, creatine kinase MB, and cardiac troponin I for diagnosis of acute myocardial infarction. Ann Clin Lab Sci 1996;26:291-300.

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[11.] Pettersson T. Ohlsson Tryding N. Increased CK MB (mass concentration) in patients without traditional evidence of acute myocardial infarction. A risk indicator of coronary death. Eur Heart J 1992;13:1387-92.

[12.] Adams JE III, Abendschein DR, Jaffe AS. Biochemical markers of myocardial injury. Is MB creatine kinase the choice for the 1990s? Circulation 1993;88:750-63.

[13.] White RW, Grande P, Califf L, Palmeri ST, Califf RM, Wagner GS. Diagnostic and prognostic significance of minimally elevated creatine kinase-MB in suspected acute myocardial infarction. Am J Cardiol 1985;1478-84.

[14.] Antman EM, Tanasijevic MJ, Thompson B, Schachtman M, McCabe CH, Cannon CP, et al. Cardiac-specific troponin I levels to predict the risk of mortality in patients with acute coronary syndromes. N Engl J Med 1996;335:1342-9.

[15.] Wu AHB, Feng YJ, Contois JH. Prognostic value of cardiac troponin I in patients with chest pain. Clin Chem 1996;42:651-2.

[16.] Missov E, Calzolan C, Pau B. High circulating levels of cardiac troponin I in human congestive heart failure [Abstract]. J Am Coll Cardiol 1996;338A:994-5.

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[22.] McLaurin MD, Apple FS, Voss, EM, Herzog CA, Sharkey SW. Cardiac troponin I, cardiac troponin T, and CK-MB in dialysis patients without ischemic heart disease: evidence of cardiac troponin T expression in skeletal muscle. Clin Chem 1997;43: 976-82.


Clinical Laboratories 812, Hennepin County Medical Center, and Departments of Laboratory Medicine and Pathology and Medicine, University of Minnesota, School of Medicine, 701 Park Ave., Minneapolis, MN 55414.

(1) Current address: Minneapolis Cardiology Associates, 1515 St. Frances Ave., Shakopee, MN 55379.

(2) Nonstandard abbreviations: AMI, acute myocardial infarction; cTn, cardiac troponin; CK-MB, creatine kinase MB; ECG, electrocardiogram; echo, echocardiogram.

* Author for correspondence. Fax 612-904-4229; e-mail
Table 1. Summary of biochemical and clinical findings for all 48
patients with minor ischemic, myocardial injury.

 Total CK CK-MB cTnl

PT Peak Minimum Peak Minimum Peak Minimum

 1 55 20 5 1 1.4 0.35
 2 68 32 2.4 1 1.8 0.35
 3 80 22 2.4 1 2.9 0.35
 4 88 40 7.9 1 9 0.35
 5 105 94 5.1 1 2.6 0.8
 6 116 53 8.8 1.6 0.9 0.35
 7 127 60 3 1 2.3 0.7
 8 130 54 14 4.6 4 0.35
 9 134 114 7.3 1.5 2.5 0.35
10 145 72 13.4 6.2 3 0.7
11 152 98 3.7 1.4 0.4 0.35
12 173 133 8.3 6.6 1.3 0.5
13 179 86 5.7 1 1.3 0.35
14 180 148 6.1 2 1.5 0.35
15 181 89 8 4.3 9.2 6.1
16 181 88 8.3 2.7 4.3 0.35
17 185 97 14.9 3.4 5.1 1.9
18 206 <20 1.2 <1.0 2.1 1.3
19 209 129 18.9 11.9 9.7 2.6
20 214 197 10.5 8.7 43.8 31.8
21 220 164 7.3 2 9 4.1
22 229 130 23.3 2.8 6.9 0.4
23 254 20 9.2 1 5.3 0.35
24 254 40 14 1 7.7 0.35
25 268 193 42.8 25.2 41.7 12.9
26 287 245 25.6 11 21.7 6.5
27 287 156 31.8 5.5 47.7 31.6
28 300 119 24.8 10.6 38.8 4
29 305 26 24.6 1 37.6 0.35
30 321 78 24.9 1.1 18.6 1.4
31 332 61 23.1 1 12 0.35
32 339 79 10 2 8.9 0.35
33 352 99 22.6 4.8 8.3 0.7
34 363 101 12.8 3.6 20.5 6.2
35 380 354 9 3.8 3.5 0.35
36 399 115 22.2 1 20.1 0.8
37 408 217 3.3 3 17.2 8.5
38 409 81 8.9 2.7 31.2 4.5
39 411 245 8.2 3.2 5.7 4.8
40 432 152 38.4 3.5 10.6 0.35
41 450 296 32.3 20.2 13.7 7.9
42 461 127 29 3.7 24 10.1
43 481 113 52.5 12.7 23.2 1.3
44 511 402 29.1 16.9 7.7 5.7
45 516 390 19.9 6.4 13.2 8.4
46 527 62 26.2 1 38.9 0.35
47 561 153 23.9 5.9 15.8 0.35
48 584 80 30.4 1 19.4 0.35


 1 Pacer Anterior WMA
 2 ST depression Anterior WMA
 3 ST depression, T inversion Anterior WMA
 4 ST elevation Inferior WMA
 5 T inversion Posterior WMA
 6 LVH, strain Inferior WMA
 7 No new changes Inferior WMA
 8 LVH, strain Inferior WMA
 9 T inversion No WMA
10 LBBB Inferior WMA
11 ST elevation No WMA
12 ST depression, T inversion Anterior WMA
13 ST depression, Q-wave No WMA
14 ST depression No WMA
15 ST elevation, Q-wave Inferior WMA
16 LVH, strain Inferior WMA
17 ST depression No WMA
18 ST depression No WMA
19 ST elevation Anterior WMA
20 No new changes Inferior WMA
21 T inversion Anterior WMA
22 ST elevation Anterior WMA
23 T inversion Anterior WMA
24 ST depression, T inversion No WMA
25 LVH, strain Anterior WMA
26 ST elevation Anterior WMA
27 ST elevation, Q-wave Inferior WMA
28 ST depression No echo
29 ST elevation, T inversion No echo
30 T inversion Inferior WMA
31 ST elevation, T inversion Anterior WMA
32 ST elevation, Q-wave Inferior WMA
33 T inversion Anterior WMA
34 ST depression, T inversion No WMA
35 ST depression No WMA
36 T inversion Posterior WMA
37 ST elevation Anterior WMA
38 ST elevation, Q-wave Inferior WMA
39 ST elevation Anterior WMA
40 T inversion No echo
41 No new changes Inferior WMA
42 T inversion No echo
43 ST elevation Anterior WMA
44 ST elevation Inferior WMA
45 ST depression No WMA
46 ST depression No echo
47 ST elevation Anterior WMA
48 ST elevation No WMA

WMA, wall motion abnormality; LVH, left ventricular hypertrophy.

Table 2. Clinical sensitivity and 95% confidence intervals
(CI) of cTnl and CK-MB mass in 48 minor, ischemic,
myocardial injury patients.

 Clinical sensitivity (95% CI), %

Hours following onset of
 chest pain CK MB cTnl

 0-6 34.2 38.9
 (21.8-54.0) (26.3-59.2)
 7-12 81.8 90.9
 (67.3-91.8) (78.3-97.5)
 13-18 75.0 92.5
 (60.8-89.9) (77.5-98.2)
 19-24 66.7 100
 (46.0-83.5) (87.2-100)
 25-36 61.5 88.5
 (44.3-82.8) (69.8-97.6)
COPYRIGHT 1997 American Association for Clinical Chemistry, Inc.
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Title Annotation:Enzymes and Protein Markers
Author:Apple, Fred S.; Falahati, Alireza; Paulsen, Pamela R.; Miller, Elizabeth A.; Sharkey, Scott W.
Publication:Clinical Chemistry
Article Type:Clinical report
Date:Nov 1, 1997
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