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Ann Thorac Surg 1997;63:879-884
© 1997 The Society of Thoracic Surgeons

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Current Review

Biochemical Markers of Myocardial Injury During Cardiac Operations

Bristol Heart Institute, University of Bristol, Bristol, United Kingdom

	Abstract

Top Footnotes Abstract Introduction Serum Biochemical Markers The Value of Serum... Other Biochemical and Histologic... Summary Acknowledgments References

 
The evaluation of myocardial damage in relation to cardiac operation from a clinical and a research perspective is of great importance, particularly for the evaluation of different cardioprotective strategies. Although measurements of serum biochemical markers have often been used, their value has been limited by their lack of sensitivity and specificity in the presence of skeletal muscle damage. A newer range of markers are now available that may reliably indicate both perioperative myocardial infarction, as well as more subtle degrees of subclinical myocyte injury. In this review, the application of biochemical markers for clinical and research purposes during cardiac operation is considered.

	Introduction

Top Footnotes Abstract Introduction Serum Biochemical Markers The Value of Serum... Other Biochemical and Histologic... Summary Acknowledgments References

 
Preservation of myocardial function has been central to the practice of cardiac surgery since its inception, and improvements in cardioprotective strategies can only be demonstrated by accurate documentation of perioperative myocardial injury. Clinical end points such as mortality and perioperative infarction rates are clearly of most value in the appraisal of outcome after open heart operations. However, the relatively low incidence of these adverse events means that large cohorts of patients are required to provide sufficient power to allow adequate comparison of different techniques of myocardial protection. Therefore, other markers are required that can identify and possibly quantify the extent of myocardial injury. Hemodynamic parameters may be used to quantify myocardial function after operation using data obtained from pulmonary artery balloon catheters, nuclear ventriculography [1, 2], and micromanometery [3]. Nevertheless, these techniques are invasive and carry potential morbidity that does not favor their application in routine practice or large randomized trials. Although transesophageal echocardiography can be used to examine left ventricular function and regional wall motion less invasively, it may lack the sensitivity to detect more subtle degrees of myocardial injury. Electrocardiographic changes and creatinine kinase measurements are noninvasive tests and are useful in the diagnosis of acute myocardial infarction [4, 5]. However, concerns with respect to their sensitivity and specificity limit their value after cardiac operations. A newer range of markers are now available, some of which are able to identify subtle degrees of myocyte injury even in the presence of skeletal muscle damage. The purpose of this review is to discuss the range of different markers available for the diagnosis of perioperative myocardial injury, and to evaluate their uses and limitations in relation to cardiac operations.

	Serum Biochemical Markers

Top Footnotes Abstract Introduction Serum Biochemical Markers The Value of Serum... Other Biochemical and Histologic... Summary Acknowledgments References

 
A number of serum biochemical markers are recognized, which include the enzymatic biochemical markers lactate dehydrogenase, enolase, creatinine kinase, and glycogen phosphorylase; the nonenzymatic cytoplasmic biochemical markers myoglobin and the fatty acid-binding protein heart isoform (hFABP); and the nonenzymatic noncytoplasmic biochemical markers myosin chains and troponin. The major limitation of many of them is their nonspecific release from damaged skeletal muscle as well as from the myocardium after cardiac operation [4, 5]. This is particularly true of enzymatic markers (eg, aspartate transaminase, lactate dehydrogenase, and enolase), which therefore, are of limited use in the identification of perioperative myocardial injury.

Creatinine Kinase
Creatinine kinase (CK) catalyzes the transfer of high-energy phosphate from adenosine triphosphate to produce creatine phosphate [6]. Creatinine kinase is not excreted in the urine and its levels are not influenced by changes in renal or hepatic blood flow in animals. Inactivation occurs in the lymphatics by proteolysis. The classification of isoenzymes is based on the presence of two subunits (M and B). Creatinine kinase MM is located mainly in striated muscle, CK-BB is most abundant in the brain, and CK-MB is found in the heart [7]. The majority of patients undergoing cardiac operation show an abnormal CK-MB release [8] within 6 to 8 hours, returning to normal within 2 to 3 days. This profile is seen earlier than after acute myocardial infarction. On the other hand, total CK level tends to increase later after cardiac operation, peaking around 21 hours, returning to normal within 5 days [9].

In addition to these isoenzymes, isoenzyme subforms, known as isoforms, have been identified (MB₁, MB₂). The absolute serum level of CK-MB₂ and the ratio of CK-MB₂ to CK-MB₁ allow earlier and more precise diagnosis of perioperative myocardial injury compared with CK-MB [10, 11]. Their only limitation is that at present they require technically demanding electrophoretic analysis for their determination [11].

Troponin
The troponins (T, I, and C) are a group of intimately related regulatory proteins located in striated muscle [12, 13]. In cardiac muscle, they are tightly bound to the contractile apparatus and, therefore, plasma levels are extremely low [13, 14]. However, with acute myocardial injury, there is a biphasic release of troponin into the serum. Troponin in the cell, presumed to originate from the cytoplasm, is released within 3 to 5 hours after loss of membrane function [15]. A late phase of continued release of troponin for 5 days or more follows and is associated with destruction of the contractile apparatus and cell death. The sensitivity of the troponins for the evaluation of myocardial injury is greater than that of CK-MB because of the wide diagnostic window that they possess. The specificity of these proteins is demonstrated by the observation that sternotomy alone does not produce a detectable increase in troponin concentrations [15]. Although some cross-reactivity does exist between the myocardial and skeletal isoforms of troponin T, modern monoclonal assays are able to reduce this to less than 1% [16].

Cardiac troponin I is confined solely to the myocardium within a few months of birth and is believed to be even more specific for myocardial injury than troponin T [17, 18]. Another advantage of troponin I measurement is that, unlike troponin T, its level is not elevated in patients with renal impairment [19].

Glycogen Phosphorylase
Glycogen 6-phosphorylase (G6P) is the key enzyme for glycogenolysis and exists as three isoenzymes: BB (brain), MM (muscle), and LL (liver). The isoenzyme G6-BB is also found in the myocardium, where it is the predominant phenotype, whereas skeletal muscle contains only G6P-MM [20]. Glycogenolysis is significantly increased in the ischemic myocardium and large amounts of G6P-BB are released into the circulation under these circumstances [21]. Cross-reaction of the assay with MM and LL isoenzymes is less than 1% [22], and hemoglobin and bilirubin do not interfere with the assay. Peak concentrations occur earlier than CK-MB or troponin T [23]. Preliminary data indicate that G6P and G6P-BB catalytic concentrations are sensitive markers of perioperative myocardial injury in patients undergoing coronary artery bypass grafting. Mair and colleagues [23] demonstrated that G6P-BB mass concentrations are even more sensitive for myocardial injury than G6P-BB catalytic activity. Further studies are required, however, to evaluate the use of this marker in the perioperative period and it may represent an effective marker of perioperative myocardial injury. Like troponin T, however, results may be unreliable in the presence of renal impairment, or cerebral injury.

Myoglobin
Myoglobin is a low-molecular weight cytoplasmic heme protein found in cardiac and skeletal muscle [4]. It is released rapidly after myocyte cell membrane disruption and therefore, is of value in the timing of cell injury to the perioperative period. Myoglobin should be measured in the coronary sinus to improve specificity when skeletal muscle injury is present. Simultaneous measurement of carbonic anhydrase III and myoglobin may also improve specificity. Skeletal muscle injury results in the release of both myoglobin and carbonic anhydrase III, thus their ratio remains constant in the serum. Myocardial injury is associated with a predominant release of myoglobin [24].

Fatty-Acid–Binding Proteins
These proteins also represent an early marker of myocyte injury. The isoform found in heart (h-FABP) has a unique structure, with only small amounts detectable in skeletal muscle and kidney [25]. Serum and urine levels are elevated in humans after myocardial infarction. Van Nieuwenhoven and co-workers [26] suggest the use of plasma myoglobin/FABP ratio to distinguish the extent of myocardial and skeletal muscle injury after open heart operation. Because the clearance of these markers is rapid, application of this ratio in clinical or experimental protocols requires frequent and early sampling and rapid assays, the latter of which is not widely available for FABP at present. A new monoclonal assay for FABP is currently being developed [27].

	The Value of Serum Markers

Top Footnotes Abstract Introduction Serum Biochemical Markers The Value of Serum... Other Biochemical and Histologic... Summary Acknowledgments References

 
Serum markers offer a simple, easily accessible clinical and research tool applicable to a wide variety of situations. They allow more accurate diagnosis of perioperative myocardial infarction, identification of more subtle myocardial injury, and the comparison of different anesthetic, surgical, and cardioprotective strategies.

Diagnosis of Perioperative Myocardial Infarction
The incidence of perioperative myocardial infarction after a coronary artery operation ranges from 2% and 26% in different reports [9]. These values have been derived mostly from electrocardiographic data and the concurrent CK-MB activity measurement (Table 1). Creatinine kinase-MB activity less than 20 U/L and the absence of any acute electrocardiographic changes suggests uncomplicated cardiac operation, whereas activity more than 50 U/L is found after Q-wave infarction [28]. The identification of intermediate degrees of myocardial injury are much more difficult to define. Creatinine kinase-MB mass concentrations have improved the diagnostic performance after acute myocardial infarction in nonsurgical patients and has been assessed by Mair and co-worker [29] after coronary artery bypass grafting. They showed that in patients without perioperative myocardial infarction, peak values of CK-MB were less than 45 µg/L 12 to 20 hours after reperfusion. In patients with perioperative myocardial infarction, CK-MB level peaked at 16 to 20 hours with values as high as 99 to 662 µg/L. Lee and Goldman [30] suggest that prolonged elevation of CK-MB mass beyond 18 hours may also be indicative of perioperative infarction. Creatinine kinase-MB isoforms are much more useful than CK-MB for reasons already alluded to and should be used in preference to CK-MB after open heart operations.

The threshold for the diagnosis of myocardial infarction after cardiac operation using troponin I assays still requires clarification and is confused further by the range of assays for troponin I currently available, all of which have different diagnostic thresholds. Using the Sanofi assay (Sanofi Diagnostics Pasteur, Guildford, UK), we have found that a peak troponin I release less than 0.5 µg/L within 48 hours of reperfusion excludes perioperative myocardial infarction after coronary artery grafting.

The prolonged release profile of the troponins implies that elevations reflect a summation of preoperative, perioperative, and postoperative events. This may limit their ability to allow detection of perioperative injury alone. Creatinine kinase-MB isoforms, and possibly even myoglobin, have a more rapid clearance and may provide more accurate timing of cellular injury [32].

Recognition of Subclinical Myocardial Injury
There is evidence that suggests that cardiac troponin T and I can reliably quantify subclinical myocardial injury. Elevated levels of troponin T have been found in up to 30% of patients with unstable angina [12] and after cardiac operation [28, 31], even in the absence of other clinical and biochemical evidence of myocardial cell necrosis. Cardiac troponin I release has been shown to correlate closely with ischemic time [33] and to differentiate the subtle differences in subclinical perioperative injury that occur in patients with diseased coronary arteries compared to patients with normal coronary arteries undergoing aortic valve replacement.

Creatinine kinase-MB isoforms may also identify subclinical myocyte injury at a level that would be undetectable by conventional CK-MB measurement [32]. Anderson and co-workers [32] used CK-MB and CK-MB₂ to compare the use of cold blood cardioplegia with intermittent ventricular fibrillation and ischemia in 40 patients undergoing coronary artery grafting. Although there was no difference between the groups when area under the time activity curve analysis was compared, peak CK-MB₂ levels were significantly higher in the cardioplegia group. This difference was not detected by CK-MB. The investigators suggest that several small peaks in the CK-MB₂ may occur during the ventricular fibrillation technique, resulting in the apparent disparity between peak release and cumulative release. In addition, because of the shorter half-life of CK-MB isoforms, they may identify more accurately the timing of cellular injury, in contrast to the troponins that measure a combination of preoperative, perioperative, and postoperative injury.

The most useful application of these markers has been for the comparison of different cardioprotective strategies [32, 34–36]. Although these studies are relatively inexpensive and easy to implement, care must be taken in their design. The release of troponin and other markers are often massive in the presence of perioperative myocardial infarction and this can produce skewing of the results. The incidence of perioperative infarction after coronary artery grafting is multifactorial and although randomization should distribute these influences equally between the groups, small population sizes do not allow for this. In a small study of 20 patients, comparing troponin T release in patients undergoing coronary artery grafting using intermittent arrest or cold crystalloid cardioplegia, Taggart and co-workers [37] excluded patients with evidence of perioperative infarction from their analysis. Therefore, although serum troponin measurements can be used in the assessment of subclinical myocardial damage and in the diagnosis of established infarction, analysis of the results in both groups of patients must be undertaken separately unless the power of the study is sufficient to allow statistical comparison of the incidence of infarction between groups.

Comparison of results should involve the analysis not only of the kinetics of marker release, but also the peak and cumulative release of substrate during the study period. Cumulative release is derived by calculating the area under the kinetic release curve and represents a summation of myocyte injury. Thus, the timing of samples is crucial for the quantitation of these measurements. In a study in our institution, troponin T and I were used to investigate the effects of normothermic, moderately hypothermic, and hypothermic systemic perfusion on cold myocardial protection in 45 patients undergoing coronary artery bypass grafting. Troponin T peaked as early as 6 hours after cross-clamp removal and troponin I peaked between 8 and 12 hours. All patients demonstrated a subsequent decline, but troponin release remained significantly elevated even at 48 hours (Fig 1). Peak and cumulative release was not affected by systemic perfusion temperature. Thus, when using these markers for the comparison of myocardial protection techniques, early sampling is required. The total period of sampling has been debated and is often based on a compromise between the desire for complete scientific data and economic considerations [38]. Sampling for at least 48 hours may be required to prevent underestimation of cumulative substrate release.

View larger version (21K): [in this window] [in a new window]   Fig 1. . Kinetics of troponin release in 45 patients undergoing routine coronary artery operations.

The evaluation of troponin T release in heart transplant donors has been shown to predict inotrope requirements after transplantation [42]. This may be useful when considering the harvesting of hearts from so-called high-risk donors in an attempt to increase the donor pool. Zimmerman and co-workers [43] examined troponin T release during the first 3 months after heart transplantation. Troponin T levels reached a peak 7 days after transplantation, and remained elevated for 43 days. Interestingly, cumulative troponin T level was not found to be a useful predictor of rejection.

	Other Biochemical and Histologic Markers of Myocardial Injury

Top Footnotes Abstract Introduction Serum Biochemical Markers The Value of Serum... Other Biochemical and Histologic... Summary Acknowledgments References

 
Measuring systemic levels of biochemical markers is limited by the fact that they can only represent the cumulative effects of perioperative events on myocardial injury and do not allow the timing of injury to specific operative interventions. Alternatively, more acute changes in myocardial function can be derived by evaluating the degree of myocardial ischemia that occurs at different times intraoperatively. This can be achieved by measuring myocardial oxygen consumption and a variety of substances that are involved in intermediary metabolism and in general, require the sampling of serum directly from myocardial effluent blood.

Myocardial ischemia during aortic cross-clamping results in altered metabolic activity and myocardial oxygen extraction, lactate production [1, 44], and acidosis have been used to compare myocardial protection strategies [45–47]. Myocardial oxygen extraction can be measured easily by calculating the difference in oxygen content of inflow perfusate (arterial or cardioplegia) and coronary venous blood, although it should be remembered that during retrograde delivery of cardioplegia, coronary venous blood is obtained from the aortic root. Changes in pH can also be measured in this way, but the use of intramyocardial probes offer the advantage of continuous monitoring during operation and has been shown to correlate closely with intracellular changes measured using sophisticated nuclear magnetic resonance techniques [48, 49]. However, application of these probes is limited as they only measure regional changes, but this can be overcome by measuring from multiple sites.

Reperfusion of the myocardium after a period of ischemia may be associated with myocyte damage and the production of various biochemical markers such as fluorescent lipoperoxidation products, reduced and oxidized glutathione, superoxide dismutase, and other markers, which have all been used to quantify myocardial injury in a number of clinical studies [46, 50, 51].

Sampling of myocardial tissue can also be used to investigate changes in cellular metabolic function and structural changes associated with ischemia. It is believed that the ability of the myocardium to maintain and replenish high-energy phosphate stores is crucial to the prevention of myocyte injury and alterations in intracellular adenine nucleotide metabolism in biopsy specimens has been used in many studies as an indicator of the efficiency of mitochondrial function [1, 52]. Suleiman and co-workers [53] have shown that patients undergoing coronary artery grafting suffer a loss in intracellular taurine and other amino acids during ischemia. Indeed, concentrations of some amino acids in the blood are increased after acute myocardial infarction [54], unstable angina [55], and cardiac operation [56]. The use of amino acids as markers of ischemia needs further evaluation.

Electron microscopy can be used to estimate structural changes occurring in mitochondria, nuclei, and the T-tubular system, as well as quantify the degree of disorganization of the myofilaments. In addition, immunohistochemistry allows visualization of proteins such as myosin, actin, tropomyosin, and troponin T [57]. However, these studies require relatively large amounts of tissue and are of limited use for clinical studies in humans. Using a technique requiring relatively small amounts of myocardial tissue in patients undergoing elective coronary artery grafting Rainio and co-workers [58] found that ischemia resulted in mitochondrial swelling, damage to the capillary endothelium, clearing of the nucleoplasm, and margination of chromatin.

Inflammatory markers may be increased in the early phase of cell injury and may be useful for identifying reversible injury. Ischemic damage results in endothelial cell injury and activation of leukocytes, and elastase concentrations in the coronary sinus (or in the case of retrograde cardioplegic delivery, from the aortic root effluent) have been used to quantify this injury [46]. Elevations of C-reactive protein and serum amyloid A protein have been found in patients with unstable angina who did not have evidence of troponin T release [11] and were linked to unfavorable outcome. The efficacy of these markers in the perioperative period is unknown at present.

The techniques mentioned above offer the potential advantage that they can be used to detect very subtle early changes in myocyte function and ultrastructure during and after ischemic injury. Some of them are very sophisticated and their uses are usually confined to research laboratories. In addition, as is the case for all "surrogate" measures of myocardial injury, care needs to be exercised when extrapolating results obtained into changes in clinical practice [59]. Ideally, studies comparing cardioprotective strategies should be designed to look at a number of clinical and hemodynamic measures of myocardial function as well as biochemical evidence of injury to be of greatest value.

	Summary

Top Footnotes Abstract Introduction Serum Biochemical Markers The Value of Serum... Other Biochemical and Histologic... Summary Acknowledgments References

 
There are a number of methods for assessing myocardial damage during open heart operation. Clinical end points are of limited value when comparing small numbers of patients because of their infrequent occurrence. Cardiac troponin and CK-MB isoforms have emerged as highly sensitive and specific markers of even subtle degrees of injury and may serve as alternative, although surrogate markers of perioperative injury. The presence of concurrent skeletal injury after open heart operations is no longer problematic in this endeavor. Serum markers may also be of value in the assessment of prognosis, particularly with regard to the outcome of patients with unstable angina. The implications for alterations in clinical and therapeutic pathways will require careful investigation using large controlled trials to be evaluated effectively. Protocols that are designed to evaluate subclinical injury will be confused by the inclusion of patients with overt infarction. Investigators using these markers will need to temper their enthusiasm with a clear understanding of not only the potential value, but also the pitfalls and limitations of their application and extrapolation to clinical practice.

	Acknowledgments

Top Footnotes Abstract Introduction Serum Biochemical Markers The Value of Serum... Other Biochemical and Histologic... Summary Acknowledgments References

 
We thank the Garfield Weston Trust and the British Heart Foundation for their support.

	Footnotes

Top Footnotes Abstract Introduction Serum Biochemical Markers The Value of Serum... Other Biochemical and Histologic... Summary Acknowledgments References

 
Address reprint requests to Mr Bryan, Bristol Heart Institute, Bristol Royal Infirmary, Bristol BS2 8HW, United Kingdom.

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Top Footnotes Abstract Introduction Serum Biochemical Markers The Value of Serum... Other Biochemical and Histologic... Summary Acknowledgments References

 

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