Creatine Kinase
Three isoenzymes of creatine kinase (CK) exist: MM (skeletal muscle type), BB (brain type), and MB (myocardial band). The CK-MB isoenzyme was the diagnostic marker of choice for ACS until the introduction of cardiac-specific troponins in the early 1990s.36,37
CK-MB is an intracellular carrier protein for high-energy phosphates, found in higher concentrations in the myocardium than are the other CK isoenzymes.11 CK-MB accounts for about 15% of total CK, but it also exists in skeletal muscle and to a lesser extent in the small intestine, diaphragm, uterus, and prostate.21 As with most cardiac biomarkers, cardiospecificity of CK-MB is not 100%, and false-positive elevations can occur in a multitude of clinical settings, including significant musculoskeletal injury, heavy exertion, and myopathies.11
CK-MB is detectable three to four hours after myocardial injury, peaks at 24 hours, and returns to normal in 48 to 72 hours. CK-MB may be used to evaluate for ACS if cardiac troponin assays are not accessible,21 but its usefulness is limited during the early hours of ACS onset and after 72 hours.
The relative index of CK-MB to total CK (CK-MB/CK) can help the clinician assess whether the rise in CK-MB is attributable to a skeletal muscle source (CK-MB/CK < 3) or a cardiac source (CK-MB/CK > 5, indicating myocardial release of CK-MB). A relative index that falls between 3 and 5 warrants further investigation with serial analyses.36 It may also be helpful to know that a CK-MB elevation associated with skeletal muscle release tends to persist and plateau over a period of several days—as opposed to CK-MB elevation with a myocardial source, which follows the time course stated above.21
In a 2006 study that included nearly 30,000 patients, it was found that 28% of those with ACS had conflicting results between troponin levels and CK-MB.38 Patients with no elevations in cardiac troponins but elevations in CK-MB had no significant increased risk for in-hospital mortality, compared with patients with negative results for both markers. Thus, an isolated elevation in CK-MB has limited prognostic value in patients with negative troponin levels.
By contrast, however, Lim et al39 recently found that elevations in CK-MB were closely associated with perioperative necrosis and MI after percutaneous coronary intervention (PCI) as a result of currently oversensitive thresholds for cTnI. Thus, CK-MB use may play a role as an independent marker of necrosis in certain situations.
Myoglobin
Because of its small molecular size, myoglobin has timely release kinetics, with elevations appreciable before those of CK-MB or cTn.11,21 Myoglobin typically rises one to four hours after myocardial injury, peaks at six to 12 hours, and returns to normal within 24 hours. For this reason, it has held special interest as an early marker of cardiac injury.
With its early release/degradation kinetics, myoglobin may serve as a marker for reinfarction.21 It can also be used to assess further damage to the myocardium, as seen with distal thrombus embolization or coronary artery manipulation. However, troponin values provide similar information on reinfarction status.4
An established shortcoming of myoglobin as an early marker of necrosis is its lack of cardiac specificity, as it is found extensively in skeletal muscle.21 Patients who present with inflammation, trauma, or significant skeletal muscle injury can have extremely high levels of serum myoglobin without myocardial involvement. Since 2000, when cTn was designated the myocardial biomarker of choice (according to the revised definition of MI, as presented that year by the European Society of Cardiology and American College of Cardiology), the use of myoglobin to identify ACS has been considered obsolete.14
NOVEL BIOMARKERS OF CARDIOVASCULAR DISEASE
Heart-Type Fatty Acid–Binding Protein
A low–molecular-weight protein, heart-type fatty acid–binding protein (H-FABP) is involved in the intracellular uptake and buffering of myocardial free fatty acids. Because its molecular size is similar to that of troponin, it is rapidly released from the cytosol and has been proposed as an early sensitive marker of acute MI.40 In a 2010 study, H-FABP was shown to be of additional prognostic value when used in conjunction with cTnI in patients at low to moderate risk for suspected ACS.41 According to the known release kinetics of H-FABP after myocardial ischemia or infarct, a rise is detectable as early as 1.5 hours after symptom onset. The marker peaks after four to six hours and, because of rapid renal clearance, returns to baseline within 20 hours.20
Interpreting results may be hindered in the patient with impaired renal function—with not only higher levels, but sustained levels of H-FABP.20 Early assays used antibodies to detect circulating H-FABP levels, but cross-reactivity occurring between other fatty acid–binding protein types have limited the clinical applications of H-FABP testing.20 As more highly specific assays are produced, more practical protocols can be implemented to confirm the presence of ACS in patients presenting early to the ED with apparent ACS.