Troponins: The New Cardiac Markers of Choice

In the hierarchy of indicators for myocardial infarction, troponins have leapfrogged creatine kinase-MB and myoglobin, says the author. He explains why, breaking down the chemistry that ties troponins to myocardial necrosis and highlighting what physicians should know about troponin assays and their clinical application.

Current guidelines for the evaluation of patients with suspected acute coronary syndromes recommend obtaining markers of myocardial necrosis as part of the initial work-up. Troponins, creatine kinase-MB (CK-MB), and myoglobin are the markers most frequently measured. Because of their higher sensitivity and specificity, troponins are now preferred as the markers of choice over CK-MB and myoglobin. This article will review what every clinician should know about the troponins—what they are, what they do in the heart, and how they are assayed.

Creatine kinase is an enzyme that catalyzes the reaction of creatine phosphate and adenosine diphosphate in muscle, yielding adenosine triphosphate (ATP) and creatine. Along with magnesium, ATP provides the energy for muscle contractions. Creatine kinase-MB, an isoform of CK, is found in high concentrations in heart muscle and is released when myocardial cells undergo necrosis. Until recently, CK-MB was considered the best marker to diagnose myocardial infarction (MI). Unfortunately, CK-MB is also found in smooth muscle, bone, and the brain. Abnormalities or injury to these other organ systems may give a false indication of myocardial injury.

Another problem with the CK-MB marker is that it is present in the blood of healthy individuals in a wide range of normal levels. It takes substantial myocardial damage to raise circulating CK-MB to pathologic levels. To be certain that myocardial necrosis has in fact occurred, one needs an absolutely high CK-MB level or a certain ratio of the CK-MB to the total CK in a blood sample.

Myoglobin, a heme-containing protein found in muscle cells, is not only one of the earliest markers for myocardial injury to appear but a relatively sensitive one as well. It is released as early as two hours post-injury and does not drop to undetectable levels for about 12 hours. Unfortunately, many conditions can provide a positive myoglobin test. Since myoglobin is found in all types of muscle, its absence is an important indicator for ruling out, rather than ruling in, myocardial injury.

Because of their superior sensitivity and specificity compared to CK-MB, cardiac troponins are now considered the best marker for myocardial cell destruction. The mere presence of troponins in the blood indicates some type of myocardial injury. The injury could be a frank MI or ongoing microinfarction from platelet emboli being released from an ulcer in a coronary artery.

Patients with microinfarction are at high risk for a complete coronary occlusion; the condition is associated with high mortality and fatal outcomes usually occur within a matter of months. In the past, it could not be detected by CK-MB assays, simply because microscopic damage does not raise CK-MB to levels outside of its normal range. More extensive myocardial necrosis is required to raise CK-MB to detectable levels.

Cardiac troponins are detectable in the blood at around the same six-hour post-injury time as CK-MB. In contrast to CK-MB, however, troponins remain detectable for up to 14 days, compared to four or five days with CK-MB. Troponins have also been reported to be elevated in myocarditis, myocardial contusion, myocardial toxicity from chemotherapy, and cardiac transplant rejection.

Troponins have by no means replaced myoglobin and CK-MB assays. The results from all three markers can provide valuable information. Understanding the timing of the rise and fall of these markers makes it possible to differentiate acute injury, subacute injury, and reinjury. The use of lactate dehydrogenase and aspartate aminotransferase, which were once assayed to help diagnose and time myocardial injury, is no longer recommended by current guidelines.

Tropomyosin's interaction with the contractile proteins actin and myosin is regulated by the troponin complex, which is made up of three distinct subunits: troponin-I, troponin-T, and troponin-C. The troponin-I and troponin-T of cardiac muscle differ structurally and therefore antigenically from their skeletal muscle counterparts. Troponin-C is the same in both types of muscle, making it an unsuitable marker for detecting cardiac muscle injury.

Troponin-C is the calcium ion receptor. Troponin-I is the inhibitory subunit that shuttles between tight binding to calcium-bound troponin-C and tight binding to actin when there is no calcium bound to troponin-C. Troponin-T acts as a kind of cement, binding itself to tropomyosin, troponin-C, and troponin-I.

What actually happens during the cardiac cycle is a very complicated sequence of events involving transient binding of calcium ions to troponin-C, transient binding of phosphate to serine residues in troponin-I, and the actual movement of tropomyosin within the grooves of actin. The final result is that the troponin complex, through transient conformational changes, inhibits or allows the direct interaction of actin and myosin, thus allowing crossbridging between these molecules to take place. In short, the presence of calcium releases troponin-I's inhibition and allows actual muscle contraction.
Recent information shows that crossbridging is not a simple "all or none" phenomenon. In reality, it is a dynamic state of weak and strong interactions. There is also an array of pumps, exchangers, and calcium channels that fine-tune these interactions. It is through knowledge of these complex phenomena that cardiac stunning, reperfusion injury, and heart failure may be better understood.




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