Use of creatine kinase to detect myocardial injury

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 creatine kinase for the diagnosis of and prognosis after acute MI will be reviewed here. Because of its pervasive availability and low cost, creatine kinase continues to be used as the primary biomarker for the diagnosis of acute MI in some regions of the world. 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 widely available. (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".)

Sex-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'.)

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 (CK-MB) for diagnostic and prognostic purposes. For most settings, it is unnecessary to obtain both values. (See "Troponin testing: Clinical use".)