INTRODUCTION — Myocardial injury is defined as the disruption of normal cardiac myocyte membrane integrity resulting in the loss into the extracellular space (including blood) of intracellular constituents including detectable levels of a variety of biologically active cytosolic and structural proteins such as troponin, creatine kinase, myoglobin, heart-type fatty acid binding protein, and lactate dehydrogenase. Injury is usually considered irreversible (cell death), but definitive proof that cell death is an inevitable consequence of the process is not available. Data indicate that very short periods of severe myocardial stress can lead to the release of cardiac troponin [1-3]. In experimental studies, release appears related to apoptotic cell death.
Causes of myocardial injury include trauma, toxins, viral infection, and catecholamines [4]. It used to be thought that ischemia or infarction consequent to an imbalance between the supply and demand of oxygen (and nutrients) was the most common cause, but clinically that is not the case. Myocardial injury without overt ischemia appears to be more common [5].
When a sufficient number of myocytes have died (myocyte necrosis) or lost function, acute clinical disease is apparent; examples include myocardial infarction (MI) or myocarditis. (See "Diagnosis of acute myocardial infarction" and "Clinical manifestations and diagnosis of myocarditis in adults".)
The biochemical characteristics and utility of myoglobin, fatty acid binding protein, lactate dehydrogenase, and creatine kinase for the diagnosis of and prognosis after acute MI will be reviewed here. Troponins, which are the preferred biomarkers for diagnosis and prognosis, are discussed separately. (See "Troponin testing: Clinical use".)
CREATINE KINASE AND CK-MB — Creatine kinase (CK) and its MB isoenzyme (CK-MB) were the most commonly used serologic tests for the diagnosis of myocardial infarction prior to the widespread adoption of troponin. Their use has markedly diminished over time. Many institutions no longer offer CK-MB testing [6]. They are discussed here predominantly for those areas of the world where cardiac troponin assays are not yet in use. (See "Troponin testing: Clinical use".)
It is difficult to find any situation in which CK-MB adds anything other than cost to the clinical utility of cardiac troponin (cTn) if that marker is used properly [7]. Thus, many recommend it no longer be used [7,8]. However, some experts continue to advocate for measurement of CK-MB in the setting of assessment of periprocedural (percutaneous coronary intervention [PCI] or coronary artery bypass graft surgery [CABG]) myocardial infarction (MI) for epidemiological reasons. Also, some clinicians prefer the use of CK-MB for the detection of early reinfarction, although this is not guideline recommended. Nonetheless, there are data to support the usefulness of cTn for each of these applications. Some have even argued that using it at all will reduce the ability of clinicians to use cTn properly [7,8].
CK basics — The enzyme CK (formerly referred to as creatine phosphokinase) exists as isoenzymes, which are dimers of M and B chains and exist in three combinations: MM, MB, and BB [9]. These isoenzymes reside in the cytosol and facilitate the egress of high-energy phosphates into and out of mitochondria. CK isoenzyme activity is distributed in many tissues, including skeletal muscle, but there is more of the CK-MB fraction in the heart [10]. Most muscles have more CK per gram than heart tissue [11,12]. Thus, skeletal muscle breakdown can lead to absolute increases in CK-MB in the plasma. In addition, in response to organ damage, including vigorous exercise [13], there is regeneration of skeletal muscle fibers and re-expression of proteins that existed during ontogeny, resulting in increased production of B chain CK protein [12,14,15]. A large percentage of the CK that is released is degraded locally or in lymph [16]. Reperfusion truncates this process and increases the rapidity and magnitude of egress of CK into plasma [17].
Total CK measurements for the detection of myocardial damage — Elevations in total serum CK lack specificity for myocardial damage, which improves with measurement of the MB fraction. The normal range of CK also varies considerably; a twofold or greater increase in the CK concentration is required for diagnosis. This criterion can be problematic in older individuals who, because of their lower muscle mass, may have low baseline serum total CK and, during MI, may have elevated serum CK-MB with values of total CK that rise but remain within the normal range [18-20]. For these reasons, total CK has not been used in the diagnosis of myocardial damage for years.
CK-MB fraction for diagnosis of acute MI — When cTn is available, CK-MB should not be used for the initial diagnosis of acute MI. If it is the only assay available, it can be used but is far less sensitive and specific.
Most assays measure CK-MB mass because they are more sensitive than activity assays. In addition, mass assays avoid, for the most part, detection of macrokinases (CK linked to IgG and dimers of mitochondrial CK) that can confound diagnosis with activity assays. The presence of macrokinases should be considered as one possibility when CK-MB is a very high percentage (>20 percent) of total CK [21]. However, patients with chronic skeletal muscle disease often have falsely positive CK-MB results when percentage criteria are used [15,22-24]. The proportion of CK that is CK-MB can be as high as 50 percent with chronic skeletal muscle injury, such as dermatomyositis/polymyositis, due to increased production of B chain CK protein [12,15,22].
Specificity and sensitivity — CK-MB was originally thought to have high specificity for cardiac tissue and was the preferred marker of myocardial injury for many years [21]. CK-MB typically begins to rise four to six hours after the onset of infarction but is not elevated in all patients until about 12 hours (figure 1) [25,26].
An elevated CK-MB is relatively specific for myocardial injury, particularly in patients with ischemic symptoms, when skeletal muscle damage is not present. Elevations return to baseline within 36 to 48 hours, in contrast to elevations in troponin, which can persist for as long as 10 to 14 days [27]. This means that CK-MB, unlike troponins, cannot be used for the late diagnosis of an acute MI but can be used to suggest infarct extension if levels rise again after declining. (See "Diagnosis of acute myocardial infarction".)
Gender specific values are essential for diagnostic use [28].
Because CK-MB can be released from skeletal muscle, its diagnostic use is impaired when skeletal muscle injury is present [29]. Some have suggested using a ratio of CK-MB to total CK to improve specificity, but that approach markedly reduces the sensitivity.
Reinfarction and late diagnosis — Since CK-MB levels return to baseline 36 to 48 hours after infarction, resampling can be used to detect very early reinfarction. Since cTn does not normalize that rapidly, it has been suggested that CK-MB might be of value in this area. It is now clear that cTn increases rapidly, albeit from an abnormal baseline in patients with reinfarction.
After myocardial revascularization — CK-MB still has advocates for its use to define MI after myocardial revascularization with either PCI or CABG. As it detects larger infarcts, CK-MB holds more “weight” with some clinicians and trialists.
Why troponin is preferred — Because of their increased sensitivity and specificity compared with CK-MB and other markers, troponins are preferred for the diagnosis of MI and for prognosis after MI. (See "Troponin testing: Clinical use", section on 'Diagnosis of acute MI'.)
MYOGLOBIN — Myoglobin is a ubiquitous heme protein that is rapidly released from damaged tissue because of its small size [30]. Its half-life in plasma is in the range of nine minutes [31]. Due to its early appearance in the serum, myoglobin was postulated to be a useful adjunct to either troponin or creatine kinase MB (CK-MB) for the early diagnosis of myocardial infarction (MI) [32]. (See "Initial evaluation and management of suspected acute coronary syndrome (myocardial infarction, unstable angina) in the emergency department".)
With contemporary, highly sensitive cardiac troponin (cTn) assays and the use of the 99th percentile or 10 percent coefficient of variation cut-off, cTn is elevated prior to elevations in myoglobin [33-35]. Thus, there is little advantage for the use of myoglobin as a marker of early injury unless an insensitive cTn assay is being employed. (See "Troponin testing: Clinical use".) In addition, the prior use of myoglobin and/or biomarkers in general for the detection of reperfusion is no longer used. Thus, this marker no longer should be used.
LACTATE DEHYDROGENASE — Lactate dehydrogenase (LD, formerly abbreviated LDH) was commonly used in the past in combination with aspartate aminotransferase (AST or SGOT) and creatine kinase MB (CK-MB) to diagnose an acute myocardial infarction (MI).
LD consists of M (muscle) and H (heart) subunits that give rise to five isoenzymes [36]. The heart primarily contains LD1 and some LD2. Red cells, kidney, stomach, and pancreas are other important sources of LD1. In contrast, LD5 predominates in skeletal muscle and liver [37].
LD activity rises to abnormal levels approximately 10 hours after the onset of MI, peaks at 24 to 48 hours, and remains elevated for six to eight days [38]. However, since troponins are more specific than LD and remain elevated for 5 to 10 days, current recommendations suggest that LD no longer has a role in the diagnosis of MI [39].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Non-ST-elevation acute coronary syndromes (non-ST-elevation myocardial infarction)" and "Society guideline links: ST-elevation myocardial infarction (STEMI)".)
SUMMARY
●We recommend using cardiac troponins in preference to creatine kinase MB for diagnostic and prognostic purposes. For most settings, it is unnecessary to obtain both values. (See "Troponin testing: Clinical use".)
●Myoglobin and lactate dehydrogenase should no longer be used for the evaluation of patients with acute coronary syndrome and/or possible acute myocardial infarction. While there are theoretical advantages of other cardiac biomarkers, such heart-type fatty acid binding protein and copeptin, available data suggest that cardiac troponin outperforms each of them in almost every specific way. Their use is not encouraged.
1 : Myocardial ischemia induced by rapid atrial pacing causes troponin T release detectable by a highly sensitive assay: insights from a coronary sinus sampling study.
2 : Brief Myocardial Ischemia Produces Cardiac Troponin I Release and Focal Myocyte Apoptosis in the Absence of Pathological Infarction in Swine.
3 : Troponin Release and Reversible Left Ventricular Dysfunction After Transient Pressure Overload.
4 : Quantifying the added value of a diagnostic test or marker.
5 : Implications of Introducing High-Sensitivity Cardiac Troponin T Into Clinical Practice: Data From the SWEDEHEART Registry.
6 : Eliminating Creatine Kinase-Myocardial Band Testing in Suspected Acute Coronary Syndrome: A Value-Based Quality Improvement.
7 : Requiem for a heavyweight: the demise of creatine kinase-MB.
8 : ESC Study Group on Cardiac Biomarkers of the Association for Acute CardioVascular Care: A fond farewell at the retirement of CKMB.
9 : The creatine-creatine phosphate energy shuttle.
10 : Specificity of elevated serum MB creatine phosphokinase activity in the diagnosis of acute myocardial infarction.
11 : Specificity of elevated serum MB creatine phosphokinase activity in the diagnosis of acute myocardial infarction.
12 : Tissue-specific distribution and developmental regulation of M and B creatine kinase mRNAs.
13 : Elevated skeletal muscle creatine kinase MB isoenzyme levels in marathon runners.
14 : Regulation of expression of M, B, and mitochondrial creatine kinase mRNAs in the left ventricle after pressure overload in rats.
15 : Abnormalities in serum enzymes in skeletal muscle diseases.
16 : Effects of lymphatic transport of enzyme on plasma creatine kinase time-activity curves after myocardial infarction in dogs.
17 : Effects of coronary artery reperfusion on myocardial infarct size calculated from creatine kinase.
18 : Diagnostic problem in acute myocardial infarction: CK-MB in the absence of abnormally elevated total creatine kinase levels.
19 : Implications of increased myocardial isoenzyme level in the presence of normal serum creatine kinase activity.
20 : Significance of elevated MB isoenzyme with normal creatine kinase in acute myocardial infarction.
21 : Biochemical markers of myocardial injury. Is MB creatine kinase the choice for the 1990s?
22 : Creatine kinase MB isoenzyme in dermatomyositis: a noncardiac source.
23 : Increase in creatine kinase MB isoenzyme levels after spinal surgery.
24 : Troponin I Assessment of Cardiac Involvement in Patients With Connective Tissue Disease and an Elevated Creatine Kinase MB Isoform Report of Four Cases and Review of the Literature.
25 : Early diagnosis of acute myocardial infarction based on assay for subforms of creatine kinase-MB.
26 : Use of a rapid assay of subforms of creatine kinase MB to diagnose or rule out acute myocardial infarction.
27 : Comparative sensitivity of cardiac troponin I and lactate dehydrogenase isoenzymes for diagnosing acute myocardial infarction.
28 : Plasma 99th percentile reference limits for cardiac troponin and creatine kinase MB mass for use with European Society of Cardiology/American College of Cardiology consensus recommendations.
29 : Effect of recent cocaine use on the specificity of cardiac markers for diagnosis of acute myocardial infarction.
30 : Effect of recent cocaine use on the specificity of cardiac markers for diagnosis of acute myocardial infarction.
31 : Rapid renal clearance of immunoreactive canine plasma myoglobin.
32 : Ninety-minute exclusion of acute myocardial infarction by use of quantitative point-of-care testing of myoglobin and troponin I.
33 : Diagnostic value of serial measurement of cardiac markers in patients with chest pain: limited value of adding myoglobin to troponin I for exclusion of myocardial infarction.
34 : Improved early risk stratification and diagnosis of myocardial infarction, using a novel troponin I assay concept.
35 : Effects of contemporary troponin assay sensitivity on the utility of the early markers myoglobin and CKMB isoforms in evaluating patients with possible acute myocardial infarction.
36 : Electrophoresis of serum isoenzymes and proteins following acute myocardial infarction.
37 : Receptor-mediated endocytosis of lactate dehydrogenase M4 by liver macrophages: a mechanism for elimination of enzymes from plasma. Evidence for competition by creatine kinase MM, adenylate kinase, malate, and alcohol dehydrogenase.
38 : Heart-type fatty acid-binding protein predicts long-term mortality after acute coronary syndrome and identifies high-risk patients across the range of troponin values.
39 : Third universal definition of myocardial infarction.