Creatinine-kinase-MB determination in non-cardiac trauma: its difference with cardiac infarction and its restricted use in trauma situations.

Cardiac injuries can be life threatening. The possibility of late complications urges the practitioner to search for any evidence of cardiac trauma. But the diagnosis of cardiac injury remains difficult. Electrocardiography and cardiac enzyme determination are most widely used, because they are readily available. Many studies advocate creatine-kinase-MB (CK-MB) isoenzyme levels as a sensitive test for cardiac contusion. Others have discarded CK-MB testing as useless in trauma situations. An elevated CK-MB value in haemodynamically stable patients may confuse the individual practitioner. To better clarify its role we investigated the course of CK/CK-MB release after trauma, with no or only a very small chance of cardiac injury and compared it with patients with severe chest trauma having cardiac complications. A total of 25 trauma patients with only skeletal muscle injury were studied. Blood samples were taken during the first 4 days after trauma. These results were compared with those of a group of 91 consecutive patients with severe chest injury, including 10 with cardiac complications. Initial results in skeletal trauma patients were indicative of cardiac injury (CK > 5% of total CK and at least 20 U/l) in 10 patients. These findings were identical to those found in patients with severe chest injury having cardiac complications. CK/CK-MB tests are frequently positive after trauma without cardiac injury, even when selective criteria are used. The time each isoenzyme is released from muscle tissue after trauma greatly influences the outcome of the test. As this release does not occur at the same moment for each isoenzyme, the test result is very much time-dependent. As a result of these findings CK-MB testing tends to cause more confusion than clarification in trauma situations. We therefore eliminated CK-MB testing from our trauma protocol as a screening investigation for cardiac injury.     

Differential diagnosis of patients with abnormal serum creatine kinase isoenzymes

For the diagnosis of myocardial injury, particularly AMI, CK-MB has become the gold standard. Changing CK-MB activities in serially collected blood from patients with suggestive signs and symptoms of AMI is almost pathognomonic for infarction. Nevertheless, an increased CK-MB cannot be equated with AMI owing to the many other types of inflammatory, traumatic, and miscellaneous forms of injury to the heart and the trace activities of CK-MB in skeletal muscle. Other enzyme tests for AMI are less efficient. In order of decreasing efficiency, the tests are CK-MB, CK, LD1 greater than LD2 or LD1/LD2 greater than 0.76, AST and LD; the latter two tests are not cost effective and add little or nothing when results for CK-MB, CK, and LD isoenzymes are available. The value of the isoforms of CK-MM and CK-MB remains to be established. Early evidence suggests that they could be helpful in the diagnosis of AMI; however, owing to the greater technical difficulties in performing these tests, their use is necessarily more restricted. Enzyme testing on admission and then every 12 hours for 2 days is sufficient and effective in making the initial diagnosis. In patients presenting early after an attack, CK and CK-MB are often normal. Decisions on AMI cannot be made on blood tests collected in the emergency department. Clot-lysing agents like streptokinase, urokinase, and tPA have changed the therapy of AMI dramatically. Enzyme tests clearly separate patients with and without successful therapeutic or spontaneous reperfusion. With successful reperfusion, the uniform finding has been a "washout" phenomenon with significantly earlier peaking times for CK and CK-MB. The isoforms of CK and myoglobin give the earliest peaks after successful reperfusion. With faster turnaround times for these tests, they may become important tools in patient management.     

Creatine kinase MB isoforms in patients with skeletal muscle injury: ramifications for early detection of acute myocardial infarction.

We measured total creatine kinase (CK), CK-MB isoenzyme, and the MB isoforms in 202 serum and plasma samples from nine groups of patients and normal individuals: 39 with acute myocardial infarction (MI), divided according to time between the onset of chest pain and blood collection (1-6 h, 7-12 h, and 13-48 h); 26 with chest pain for whom an MI was ruled out, sampled at admission; 17 undergoing bypass surgery or cardiac catheterization, sampled within 6 h after either procedure; 17 with acute skeletal muscle injury, sampled within 8 h after injury; 30 marathon runners immediately after a race; 17 runners and other athletes > 12 h after training or a race; 12 with cerebral injury or seizures, sampled at admission; 8 with closed head injury, sampled at admission; and 38 normal subjects. CK-MB (relative index) and MB isoforms (MB2/MB1) were respectively increased in 15% and 75% of MI patients 1-6 h after onset, 94% and 94% after 7-12 h, and 88% and 8% after 12 h, and in 87% and 82% of cardiac surgery patients. MB isoforms were increased in most patients with acute skeletal muscle trauma and in subjects examined after exercise, but were within normal limits in patients for whom MI was ruled out, patients with cerebral trauma, and normal individuals. The relative index of MB/total CK was normal in essentially all individuals in the last groups, including those with acute skeletal muscle trauma. We concluded that the CK-MB isoform ratio is increased in both acute skeletal muscle injury and MI. The isoform ratio is most useful for distinguishing recent from old (> 12 h) injury.     

Change in concentrations of myogenic components of serum during 93 h of strenuous physical exercise

Effects of 93 h of long, strenuous ranger training on activities of creatine kinase (CK) and lactate dehydrogenase (LD), along with their isoenzymes, and on concentration of myosin light chain were examined in sera of young soldiers. Total CK activity in serum was measured before, during, and after the training. Throughout, total CK activity in serum increased steadily. At the end of the training, activity of CK-MB was increased but its activity ratio to total CK remained unchanged; the activity ratio of LD1/LD2 also was not increased, although total LD activity was increased. Myosin light chain was increased by about fourfold at the end of the training and remained high for three days thereafter. However, its concentration was much lower than in myopathies such as polymyositis and Duchenne muscle dystrophy. The increased activities in serum of total CK and CK-MB isoenzyme on strenuous physical exercise evidently were of noncardiac origin. Although CK activity was comparable with that seen in myopathies accompanied by disintegration of skeletal muscle, the relatively low concentration of myosin light chain in serum suggests minimal skeletal muscle damage.     

Activities of key enzymes in the energy metabolism of human myocardial and skeletal muscle

Summary. Activities of total creatine kinase (CK), its isoenzyme MB (CK-MB), total lactate dehydrogenase (LD) and its isoenzyme LD₁, phosphofructokinase (PFK), asparate aminotransferase (ASAT) and citrate synthase (CS) were determined in skeletal muscle biopsies obtained from physically trained and untrained men and in myocardial biopsies from patients subjected to open heart surgery because of valve disease. The LD₁, ASAT and CS activities were higher in trained than in untrained skeletal muscle and still higher in heart muscle than in either trained or untrained skeletal muscle. The CK-MB activity was higher in trained than untrained skeletal muscle and the myocardial CK-MB activity was similar to that in trained skeletal muscle. Total CK activity was slightly lower in trained than in untrained skeletal muscle and the myocardial CK activity was approximately one third of the skeletal muscle CK. Both the PFK and the total LD activity was of similar magnitude in the different muscle types. In conclusion, as estimated by enzyme activities, the oxidative capacity is 2–3 times larger in myocardial than in skeletal muscle, while the glycolytic capacity as estimated by PFK appears to be the same.     

Differentiating muscle damage from myocardial injury by means of the serum creatine kinase (CK) isoenzyme MB mass measurement/total CK activity ratio

We immunoenzymometrically measured creatine kinase (CK) isoenzyme MB in extracts of myocardium and in homogenates of five different skeletal muscles. CK-MB concentrations in the former averaged 80.9 micrograms/g wet tissue; in the skeletal muscles it varied widely, being (e.g.) 25-fold greater in diaphragm than in psoas. CK-MB in skeletal muscles ranged from 0.9 to 44 ng/U of total CK; the mean for myocardium was 202 ng/U. In sera from 10 trauma and 36 burn patients without myocardial involvement, maximum ratios for CK-MB mass/total CK activity averaged 7 (SEM 1) ng/U and 18 (SEM 6) ng/U, respectively. Except for an infant (220 ng/U), the highest ratio we found for serum after muscular damage was 38 ng/U. In contrast, the mean maximum ratio determined in 23 cases of acute myocardial infarction exceeded 200 ng/U. Among seven determinations performed 8 to 32 h after onset of symptoms, each infarct patient demonstrated at least one ratio greater than or equal to 110 ng/U. Ratios observed after infarct were unrelated to treatment received during the acute phase. We propose a CK-MB/total CK ratio of 80 ng/U as the cutoff value for differentiating myocardial necrosis from muscular injury.     

Creatine kinase MM isoforms in serum after cardiac surgery

We evaluated creatine kinase (CK; EC 2.7.3.2) MM3:MM1 isoform ratios in the serum of cardiac patients immediately after cardiac surgery for the diagnosis of perioperative myocardial injury. The mean ratio was 4.8 (range, 1.4-10.7) in 22 patients who had postoperative myocardial complications and 4.6 (1.3-9.6) in 66 patients who did not. By the first postoperative day the ratio had decreased substantially in both groups of patients. The isoform ratio did not correlate with the concentration of total CK, CK-MB, total lactate dehydrogenase (LD), or the incidence of LD1:LD2 or LD5:LD2 ratio reversal. Of these measurements, CK-MB and LD concentrations differed most between the groups of patients; parallel testing of CK-MB and LD showed an optimized sensitivity and specificity of 77% and 87%, respectively. We conclude that analysis for CK-MM isoforms does not add information in the period immediately after cardiac surgery; concentrations of CK-MB and LD correlate with myocardial injury, but the sensitivity and specificity of these measurements may not be high enough for clinical utility.     

Muscle enzymes and isoenzymes in Emery-Dreifuss muscular dystrophy

Emery-Dreifuss muscular dystrophy (EDMD) is a rare X-linked muscular dystrophy. Creatine kinase (CK) activity usually is increased in serum of affected males, but results for aldolase and lactate dehydrogenase (LD) in serum have been inconsistent, as have those for CK in carrier females. There have been few studies of CK-MB or LD isoenzyme-1 (LD-1) in EDMD. We measured CK, CK-MB, LD, LD-1, and aldolase activity in sera of 84 members of two large families with EDMD. DNA analysis had been carried out on all subjects. Although CK, LD, and aldolase activities were significantly increased in affected males, CK activity was the most consistently increased and was the least subject to artifactual increases. Mean CK-MB in serum was mildly increased, but LD-1 was within the normal reference interval, suggesting that CK-MB is increased in skeletal muscle in EDMD, as has been found in other forms of dystrophy. CK decreased with age in affected males. We saw no significant increases of muscle enzymes or isoenzymes in 33 EDMD carriers studied, of whom 19 were obligate carriers and 14 had been identified by DNA analysis.     

Cardiac enzyme changes in myxedema coma

A 74-year-old man with myxedema and hypothermia had increased activities in plasma of creatine kinase (CK; EC 2.7.3.2), aspartate aminotransferase (AST; EC 2.6.1.1), and lactate dehydrogenase (LD; EC 1.1.1.27) and increased proportions of CK-MB (up to 20% of total CK) and LD1 isoenzymes, but no clinical or investigational evidence of associated myocardial infarction. This case illustrates that plasma enzyme activity and isoenzyme profiles in such clinical settings should be interpreted with caution, because increases in CK-MB and LD1 may relate to myxedema coma or hypothermia (or both) rather than to myocardial infarction.     

Cardiac troponins and creatine kinase content of striated muscle in common laboratory animals

Animal models are important for the investigation of human heart pathology, novel treatments, and medical or surgical interventions for disease. Serum markers of myocardial damage may also be important tools within this field of research. In order to assess the cardiac specificity of widely utilised serum markers, we measured the cardiac troponins and creatine kinase (CK) isoenzymes in cardiac and skeletal muscle samples taken from dog, monkey, pig and rat. These samples were also analysed by immunoblotting for cardiac troponin I (cTnI) and cardiac troponin T (cTnT). The content of cTnI and cTnT in skeletal muscle was below 0.6% of that found in heart for all animal species studied. This low immunoreactivity in skeletal muscle was confirmed by immunoblot analysis. The content of CK was higher in skeletal muscle than in heart muscle for all species. The CK-MB/total CK ratio was lower in skeletal muscle than in cardiac muscle for all species. The differences in CK-MB content of skeletal muscle and heart muscle were much less pronounced than the tissue differences in the amounts of the cardiac troponins. The cardiac troponins are potentially useful serum markers of myocardial damage, with high specificity for myocardial muscle in these common laboratory animals. Creatine kinase-MB is much less cardiac-specific.     

Lactate dehydrogenase isoenzyme 1: Its usefulness as a screening test in diagnosis of myocardial infarction

Immunological assay of LD-1 activity provides a quantitative measurement of the type of lactate dehydrogenase (LD, EC 1.1.1.27) activity characteristic of myocardial origin. Using this test, a laboratory diagnosis of myocardial infarction can be either ruled out or confirmed in approximately 75% of patients in whom this diagnosis is suspected, without electrophoretic separation of creatine kinase (CK, EC 2.7.3.2.) and LD isoenzymes. Normal total CK and LD activities cannot be used to rule out myocardial infarction since CK-MB and LD-1 may have increased although total activities remain within their reference ranges. LD-1 activity increases as quickly as CK-MB following the onset of pain in the majority of patients but it remains elevated longer giving a greater period of time during which the diagnosis of myocardial infarction can be confirmed.     

Human myocardial and skeletal muscle enzyme activities: creatine kinase and its isozyme MB as related to citrate synthase and muscle fibre types

Summary. Activities of myocardial and skeletal muscle total creatine kinase (CK) and its isozyme MB were related to the oxidative capacity [measured as the citrate synthase (CS) activity] and to the contractile characteristics (estimated as the percentage of type I muscle fibres). Skeletal muscle biopsies were obtained both from physically trained and untrained men and myocardial biopsies from patients subjected to open-heart surgery performed because of mitral or aortic valve disease. Enzyme activities were determined on freeze-dried muscle specimens. The CK-MB activity was about twice as high in trained skeletal muscle as in untrained ones reaching the myocardial level. The total CK activity was about three times higher in skeletal muscle than in myocardium; the myocardium, however, had CS activity 3–4 times larger than that of skeletal muscle. A close correlation was demonstrated between activities of CK-MB on one hand and CS (r= 0·76) or percentage type I fibres (r= 0·83) on the other hand suggesting a connection between CK-MB activity and the oxidative capacity of the cell. This was in contrast to total CK where different regressions were obtained when comparing the myocardium and the skeletal muscle of trained or untrained men. In conclusion, CK-MB activity in trained skeletal muscle in athletes were similar to that in myocardium. CK-MB was related to the oxidative capacity and formation of cellular energy in skeletal and heart muscle.     

Enhanced cardiac enzyme profile

A protocol for an enhanced Cardiac Enzyme Profile is proposed based on an admission, or initial, serum specimen and a second specimen 16 hours after onset of symptoms as minimal baseline serum samples in order to accomplish several simultaneous goals: 1. Detecting CK2MB at its average peak for maximal assurance of diagnosis when release is small and for prognosis in all cases of increased serum CK2MB 2. Detection of laboratory evidence of myocardial injury when admission is delayed after onset by the collection of an admission sample for declining CK2MB, and for assays of other enzymes with longer time curves after myocardial injury such as LD isoenzymes and ASAT/ALAT activities and ratio 3. Establishment of decision limits and criteria for the determination of laboratory evidence of myocardial injury 4. Providing cost-effective procedures other than limitation of the number of samples; these include establishing thresholds and criteria for total CK, total LD, and ASAT so that isoenzymes and ALAT are only performed when thresholds are exceeded and criteria are met; performing only CK and, if the threshold is exceeded, CK isoenzymes on the 16-hour sample; collecting additional samples after the first two only when indicated by positive or suspicious (borderline) results and only on routine morning or afternoon rounds rather than specifically timed specimens (except in cases involving thrombolytic therapy); and termination of the protocol once peak positive CK2MB activity and requisite diagnostic consensus confirmation (such as positive LD isoenzymes) is obtained whether or not thrombolytic therapy is involved. Tissue localization of the enzymes has been outlined in some detail with particular reference to the amount of CK2MB in skeletal muscle. Pathophysiological factors discussed in more depth in a previous article have been amplified here with particular reference to the role of increased synthesis as a response to myocardial injury by surrounding prehypertrophic and hypertrophic myocardium as a possible major source of increased serum enzymes in myocardial infarction. ASAT and especially the ASAT/ALAT ratio are useful tests in the protocol, particularly in cases tested late after onset of symptoms when CK2MB has declined into the borderline or usual range, and ASAT/ALAT may be helpful in evaluating LD isoenzyme results. Codes for interpretive comments are provided to serve as guidelines.     

Clinical effectiveness of the Du Pont aca measurement of creatine kinase MB in serum from patients in a coronary-care unit

We evaluated the clinical effectiveness of measuring creatine kinase (CK; EC 2.7.3.2) isoenzyme MB and lactate dehydrogenase (LD; EC 1.1.1.27) isoenzymes in diagnosis of acute myocardial infarction. We used an agarose electrophoresis method to measure CK and LD isoenzymes and the Du Pont aca column method to measure CK-MB. Serial blood specimens were drawn from 100 patients consecutively admitted to our Coronary Care Unit. Because of the low diagnostic specificity for CK-MB measurements by both agarose electrophoresis and the discrete-analysis method, as compared with reported values, we re-evaluated our isoenzyme data by using Receiver Operating Characteristic curves. Such analysis of the data established optimal decision levels of greater than or equal to 25 U/L and greater than or equal to 18 U/L plus greater than or equal to 6% of total CK for serum CK-MB measured by the agarose electrophoresis and the aca methods, respectively, and an optimal decision level of greater than or equal to 0.92 for the ratio of LD 1/2 measured after agarose electrophoresis. At these decision levels we obtained a sensitivity of 100%, 100%, and 95% and a specificity of 94%, 92%, and 90% for CK-MB (agarose electrophoresis), CK-MB (aca), and the LD 1/2 ratio, respectively.     

Macro creatine kinase type 1 with electrophoretic mobility identical to that of the MB isoenzyme

We describe the case of an elderly woman whose symptoms and electrocardiographic pattern initially suggested acute myocardial infarction. The value for total serum creatine kinase (EC 2.7.3.2; CK) was 737 U/L (reference interval: 22-269 U/L), and electrophoresis for CK isoenzymes demonstrated two bands, the more anodal migrating to the CK-MB region and the second migrating between the CK-MB and CK-MM regions. The above-normal total CK and electrophoretic pattern persisted during her 11-day hospital course. The QuiCK-MB (International Immunoassay Labs.) and Tandem-E CK-MB (Hybritech) immunoassays, however, showed CK-MB mass measurements within the normal range. In further investigation with a mixture of patient's serum and human-serum-based control containing all CK isoenzymes, the electrophoretic mobility of only CK-BB was altered, proving that the patient had antibody to the B unit of CK in her serum. Immunofixation revealed the more anodal band to be a CK-IgA lambda complex, and the more cathodal band, a CK-IgG kappa complex. Mixing the patient's serum with polyclonal antibody specific for CK-B slowed the electrophoretic mobility of only the more anodal band. Polyclonal antibody specific for CK-M had no effect on either band. Evidently, this patient had two different types of macro CK type 1, both containing CK-BB. We conclude that macro CK type 1 can mimic CK-MB and be a source of confusion.     

IgA-CK-BB complex with CK-MB electrophoretic mobility can lead to erroneous diagnosis of acute myocardial infarction

This patient, on admission, presented with a tentative diagnosis of myocardial infarction: the electrocardiogram showed a nonspecific ST-segment and T-wave abnormalities, and total creatine kinase (CK; EC 2.7.3.2) activity was slightly increased (238 U/L). However, a high electrophoretic value for CK-MB (50% of total CK activity) and the electrophoretic pattern of lactate dehydrogenase (EC 1.1.1.27) isoenzymes ruled out myocardial infarction. The isoenzyme migrating as CK-MB was found later to contain no immunologically normal CK-M subunits, and it was bound to IgA. A mixture of the patient's serum and a human serum control containing all CK isoenzymes showed altered electrophoretic mobility only for CK-BB, indicating that the patient's serum contained antibodies to the B unit of CK. Elution from a Sephadex G-200 column showed that the peak at which most of the anodic CK was eluted corresponded to a molecular mass of approximately 200 kDa. Evidently this atypical isoenzyme was an IgA-CK-BB complex. Because this macro CK type 1 can mimic CK-MB, it may therefore be a source of confusion.     

Changes in serum enzymes, lactate, and haptoglobin following acute physical stress in international-class athletes

Skeletal muscle is rich in creatine kinase (CK), lactate dehydrogenase (LD), and other enzymes. Many reports describe changes in serum CK and LD following exercise. In our study, 11 male international-class medium-distance runners were followed over a 10-month period prior to the 1984 US Olympic Trials. Cardiorespiratory fitness, evaluated through repetitive treadmill testing, was unchanged in our athletes. Total CK increased significantly during the course of training, and the CK-MB activity was higher than that of sedentary individuals; CK-MB never rose to more than 3% of the total CK. Total LD also rose following acute exercise; however, the proportions of the five isoenzymes were unaltered. There was no change in the LD-1/LD-2 ratio from normal. The origin of the increased serum enzymes was believed to be primarily skeletal muscle. A decrease of serum haptoglobin following acute stress was attributed to intravascular hemolysis and binding of hemoglobin. As expected, serum lactate was dramatically increased immediately postexercise.     

The specificity of biochemical markers of cardiac damage: a problem solved.

This paper reviews the tissue specificity of cardiac troponin I (cTnl), cardiac troponin T (cTnT) and creatine kinase (CK) MB in human and animal heart and skeletal muscles. Studies reveal that CK-MB can be expressed up to 20% of total CK activity in human skeletal muscle; and therefore is not 100% specific for the heart. One cTnl isoform has been described and shown to be 100% specific for the heart. While one to four cTnT isoforms are expressed in diseased and regenerating human skeletal muscle, these isoforms are not the same as the cTnT isoforms expressed in the human heart and are not detected by the cTnT diagnostic assays used in clinical practice. Representative cases are described demonstrating the role of monitoring cardiac troponins in blood for differentiating false positive CK-MB increases due to skeletal muscle injury. Further, sufficient reactivity and tissue specificity of cTnl and cTnT assays are demonstrated for use as markers of myocardial injury in laboratory animals. Monitoring cTnl and cTnT concentrations in the circulation appears poised as the new standards for detection of myocardial injury.     

免疫抑制法检测肌酸激酶同工酶活性高于肌酸激酶的临床价值分析

目的探讨免疫抑制法检测肌酸激酶同工酶(CK-MB)结果高于肌酸激酶(CK)活性的临床价值。方法回顾分析4例免疫抑制法检测CK-MB结果高于CK活性的病例,并比较心内科与脑外科心肌酶谱检测结果CK-MB/CK比值。结果结果4例病例中3例为颅脑损伤,1例为结肠癌术后,4例病例均无心肌损伤;脑外科CK-MB/CK比值明显高于心内科(P<0.05)。结论免疫抑制法检测CK-MB活性假性高于CK活性,或CK-MB/CK比值上高有重要的脑损伤警示价值。     

Lactate dehydrogenase isoenzyme-1/total ratio: accurate for determining the existence of myocardial infarction

We have gradually revised our medical protocols for measuring creatine kinase MB isoenzyme (CK-MB) and lactate dehydrogenase isoenzyme-1 (LD-1) because of identifiable problems in the use of an interpretation of CK-MB isoenzyme associated with slowly evolving or small myocardial infarct, the use of thrombolytic therapy, or burn and trauma, each of which affects the rate of appearance and composition of isoenzymes present. Despite recent evidence of the efficacy of LD-1 isoenzyme measurement in the first 12 to 24 h of myocardial infarction, this test is not widely used because of overstated assumptions about the value of CK-MB. Here we studied the adequacy of the current isoenzyme assays by determining the value of CK-MB and LD-1 at optimum serum sampling times and establishing the contribution of individual and combined predictors to diagnostic efficiency. We conclude that the LD-1/total LD activity ratio in serum is superior to measurement of CK-MB or LD-1, or both, in the diagnosis of acute myocardial infarction. Moreover, this ratio is most valuable when interpretation of the result for CK-MB isoenzyme is equivocal in patients with small or evolving myocardial infarcts.