Other Biomarkers and the Evaluation of Patients with Suspected Myocardial Ischemia

Copeptin

Copeptin is a blood biomarker that has entered the clinical arena because of the development of an analytically reliable method to measure a signal that is released stochiometrically with the biologically active vasopressin. Arginine vasopressin (AVP) plays an important role in fluid balance by mediating antidiuretic effects (thus, its previous name “antidiuretic hormone”) and vascular tone by causing strong arteriolar vasoconstriction. It is secreted as a prohormone from the pituitary gland and then cleaved from its precursor ( Figure 8-e1 ). The remaining part of the prohormone is called copeptin, and from an analytical viewpoint, it offers a distinct advantage, because it is much more stable than AVP.

The current concept is that endogenous stress is the main trigger of AVP and/or copeptin release. Because endogenous stress is already present at the onset of acute MI, copeptin has the theoretical advantage over necrosis biomarkers because it is able to identify acute ischemia and MI early after symptom onset, even when cTn (measured by a conventional assay) is still normal ( Figure 8-2 ). Because the time course of endogenous stress and detectable cardiomyocyte damage seems to be reciprocal, copeptin seems to be an ideal marker to compensate for the deficit in sensitivity with conventional cTn assays in patients who present early after the onset of MI. When used in conjunction with conventional fourth-generation cTnT, the added value of copeptin for diagnostic accuracy at the time of initial presentation is substantial ( Table 8-1 and Figure 8-3A ). These findings in a pilot study were subsequently confirmed by several large diagnostic studies, an open-label randomized management trial, and a meta-analysis that summarized findings from 14 studies in more than 9000 patients. However, the sensitivity of the cTn assay used in combination with copeptin is an important determinant of the magnitude of any incremental clinical value of copeptin. When used with conventional cTn assays, copeptin significantly increases diagnostic accuracy; however, when tested in conjunction with high-sensitivity cTn, the gain in accuracy is much smaller (see Figure 8-3B ).

Levels of copeptin are also strongly associated with the risk of death. An elevation in copeptin carried a similar associated risk of all-cause mortality with that associated with an elevation in cTn (odds ratio 5.6 vs. odds ratio 6.8, respectively). In addition, copeptin seems to modify the risk of death associated with levels of cTn ( Figure 8-4 ).

The potential application in which copeptin seems to have the greatest appeal to clinicians is its use within a dual-marker strategy for early rule-out of acute MI. Patients with acute chest pain presenting to the emergency department (ED) with negative initial values of cTn (below the 99th percentile) and also low levels of copeptin (e.g., <10 pmol/L) have a low probability of a final diagnosis of MI. Therefore, this combination of negative biomarker results yields a commensurately high negative predictive value (98% to 99% if using high-sensitivity cTn assays) for acute MI and may be considered to facilitate rapid discharge from the ED without the need for serial cTn testing. An open-label multicenter randomized controlled study that evaluated the safety and efficacy of this approach compared with standard of care (second cTn measurement after 3 to 6 hours) supported the safety of this strategy. Among 920 patients with suspected acute coronary syndrome (ACS), the rates of major adverse cardiovascular events by 30 days were 5.17% (95% confidence intervals, 3.30% to 7.65%) in the standard group and 5.19% (95% confidence intervals, 3.32% to 7.69%) in the copeptin group. The rate of adverse events in those with low copeptin who were discharged was 0.6%. However, clinicians should be aware that because of the rapid decline in copeptin after resolution of ischemia, false negative results are possible when patients present late (e.g., >6 hours) after symptoms.

Other Putative Biomarkers of Ischemia

Other biomarkers of ischemia, such as ischemia-modified albumin or unbound free-fatty acids, that have been studied for diagnostic application in patients with suspected MI have not sustained consistent evidence for incremental value and are therefore not recommended for clinical use. See the section Forward Outlook for a discussion of ongoing investigation of microRNA as a candidate biomarker family.

General Considerations

At present, biomarkers of necrosis other than cTn appear to have no additive diagnostic role for acute MI. When cTn is not available, the next best alternative is creatine kinase-MB (CK-MB) (measured by mass assay). Because CK-MB constitutes 1% to 3% of the CK in skeletal muscle and is present in minor quantities in the intestine, diaphragm, uterus and prostate, the specificity of CK-MB is impaired in the setting of major injury to these organs, especially skeletal muscle. Although of historical significance, because of their low specificities for cardiac injury, lactate dehydrogenase, aspartate aminotransferase, and total CK should not be used for the diagnosis of MI. Myoglobin shares this limitation because of its high concentration in skeletal muscle. Because of its small molecular size and rapid rise in the setting of myocardial necrosis, myoglobin has a historical interest as an early marker of MI; however, this application of myoglobin has now been shown not to add diagnostically to sensitive and high-sensitivity assays for cTn.