Introduction
Cardiac troponin (cTn) is the preferred biomarker for the evaluation of patients with suspected acute myocardial infarction (MI) (see Chapter 7 ). In addition, it makes sense that other biomarkers that reflect the varied causes and consequences of MI, such as inflammation, activation of coagulation, endothelial dysfunction, and hemodynamic stress, might contribute information that is complementary to the detection of myocyte injury with cTn. Hence, other biomarkers believed to reflect these underlying pathobiological processes have been studied extensively with respect to their ability to add to cTn for diagnosis or risk stratification. In particular, additional cardiovascular biomarkers have been proposed to help address the most important limitation of conventional cTn assays: a deficit in sensitivity within the first hours after onset of acute MI.
Despite the compelling a priori rationale and translational science behind them, few biomarkers have yet proven valuable in routine clinical practice when added to use of a contemporary assay for cTn. As such, the current clinical role of alternative biomarkers is less than what was anticipated 10 years ago. This chapter discusses the rationale for investigating cardiovascular biomarkers other than cTn and the available evidence regarding their diagnostic and prognostic applications, with more depth given to the few biomarkers that are in present clinical use for these indications in some regions of the world.
Rational Search for Cardiovascular Biomarkers
Although cTn is the prototypical cardiovascular biomarker because of its value for diagnosis and clinical decision-making, cTn and other biomarkers of necrosis are detectable only once myocardial injury has occurred, and they give no insight into the pathobiological causes of the myocardial injury. Because the increase of cTn concentrations in peripheral blood are inherently delayed by the time required for destruction of the myocyte cytoskeleton, strategies using conventional assays for cTn require serial sampling and prolonged monitoring for 6 to 12 hours in a significant number of patients (see Chapter 7 ). However, the clinical introduction of sensitive and high-sensitivity assays for cTn has substantially reduced and modified this aspect of unmet clinical need. Also, because cTn is an integral part of the definition of MI, in the absence of any other “gold standard,” diagnostic studies inherently favor cTn and render it virtually impossible for any alternative biomarker to replace cTn.
Therefore, a more likely role for alternative biomarkers is to complement rather than replace cTn in clinical practice. Theoretically, some time delay between the onset of MI (coronary plaque rupture with distal embolization and/or coronary occlusion) and the appearance of cTn as a structural protein in the peripheral circulation should still remain. In addition, because detection of circulating cTn using currently available assays signals cardiomyocyte injury regardless of the underlying cause, multiple nonischemic conditions can challenge the interpretation of increases in cTn, particularly mild increases. Therefore, alternative biomarkers that reflect other pathophysiological signals (e.g., plaque rupture and/or plaque erosion) (see Chapter 3 ), other signals that are consistently present at the onset of acute MI (e.g., endogenous stress), biomarkers that reflect myocardial ischemia without necrosis (for the detection of unstable angina), or biomarkers that are associated with a specific pathobiology present in only a subset of MI patients have the potential to help differentiate among the various subtypes of MI (particularly type I vs. type II; see Chapter 1 ) and allow more personalized and targeted patient management ( Figure 8-1 ).
Diagnostic Applications
The search for biomarkers of myocardial necrosis that are more sensitive or rise earlier than cTn has proven predominantly unsuccessful. In this author’s opinion, only one alternative biomarker, copeptin, has matured enough to currently justify possible routine clinical use for the early diagnosis of acute MI; therefore, it is discussed in greater detail.
Biomarkers Indicative of 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 ).
| Characteristics | AUC (95% CI) | AUC (95% CI) in Combination with hs-cTnT |
|---|---|---|
| hs-cTnT and hs-cTnI | 0.96 (0.94–0.98) | |
| c-TnT | 0.90 (0.86–0.94) | |
| Copeptin | 0.75 (0.69–0.81) | 0.96 (0.94–0.98) |
| Copeptin + c-TnT | 0.97 (0.95–0.98) | |
| h-FABP | 0.59 (0.48–0.70) | 0.88 (0.86–0.90) |
| sFIt-1 | 0.70 (0.64–0.76) | 0.96 (0.95–0.98) |
| PIGF | 0.60 (0.54–0.66) | 0.96 (0.95–0.98) |
| MPO | 0.63 (0.59–0.68) | 0.95 (0.92–0.97) |
| MRP8/14 | 0.65 (0.60–0.69) | 0.95 (0.92–0.97) |
| PAPP-A | 0.62 (0.57–0.67) | 0.95 (0.93–0.97) |
| CRP | 0.59 (0.54–0.64) | 0.95 (0.93–0.97) |
∗ For levels of biomarkers obtained at presentation to the emergency department.
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.
Biomarkers of Necrosis
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.
Heart-Type Fatty Acid-Binding Protein
Heart-type fatty acid-binding protein (h-FABP), a small soluble cytosolic protein involved in the transportation of long-chain fatty acids into the cardiomyocyte, is released rapidly into the circulation in the setting of cardiomyocyte injury. Because of its solubility and small size (15 kDa), h-FABP can be released more rapidly than structurally-bound molecules like cTn. Thus, h-FABP is regarded as an early sensitive marker of MI. Most of the promising data regarding the potential clinical value of h-FABP were obtained before the clinical introduction of sensitive and high-sensitivity cTn assays. When studied in conjunction with sensitive and high-sensitivity cTn, the available data are heterogeneous as to whether h-FABP provides added diagnostic value in patients presenting with suspected MI, including in the challenging subgroup of patients who present early. h-FABP is available for clinical use in some countries and is used routinely in some centers.
Biomarkers of Plaque Instability
Inflammation plays a key role in atherosclerotic plaque formation (see Chapter 3 ) and contributes to plaque destabilization and plaque disruption that precedes cardiomyocyte damage by minutes to potentially hours or days. For this reason, biomarkers of plaque instability are logical candidates to provide added value in the early diagnosis of acute MI (see Figure 8-1 ). Among the biomarkers believed to be associated with plaque instability, assays have been developed for at least six candidates that allowed their evaluation in clinical studies: C-reactive protein (CRP), myeloperoxidase (MPO), myeloid-related protein 8/14 (MRP-8/14), pregnancy-associated plasma protein-A (PAPP-A), and the angiogenetic factors vascular endothelial growth factor receptor 1, also called fms-like tyrosine kinase (Flt-1), and placental growth factor (PlGF). Despite the strong underlying pathophysiological rationale, methodologically robust diagnostic studies have not been able to show consistently compelling diagnostic clinical utility for CRP, MPO, MRP-8/14, PAPP-A, or the angiogenic markers (see Table 8-1 ). In particular, their lack of specificity for coronary arterial inflammation, or even cardiovascular inflammatory processes, has been a major limitation, resulting in extremely poor positive predictive value and a limited overall impact on diagnostic accuracy. Pertinent examples of relevant studies are discussed in more detail in the sections that follow.
Myeloperoxidase
MPO is a hemoprotein that is produced by polymorphonuclear neutrophils and macrophages in response to inflammatory stimuli, and that catalyzes the conversion of chloride and hydrogen peroxide to hypochlorite. MPO is involved in the oxidation of lipids within low-density lipoprotein particles, and it is believed to promote the formation of foam cells in atherosclerotic plaques. Inflammatory cells producing MPO are found more frequently and in higher concentrations in the culprit lesions of patients with ACS than in patients with stable disease. Together with metalloproteinases, MPO contributes to the degradation of the collagen layer of atheroma and the risk of erosion or rupture.
MPO concentration is increased in patients with coronary heart disease, with a gradient of increasing concentration among patients with stable coronary artery disease, those with unstable angina, and patients with acute MI. Elevated levels of MPO are associated with a future risk of developing coronary heart disease and a higher risk of major cardiovascular events in patients who present with ACS. In a cohort of 604 patients who presented with suspected ACS, increasing concentrations of MPO were associated with a higher risk of major cardiovascular events and a greater likelihood of a final diagnosis of unstable angina or MI. On the basis of these findings, high-throughput assays for MPO for clinical use were introduced. However, in practice, MPO had limited clinical use because of its lack of clinical specificity. MPO concentrations are elevated whenever there is activation of neutrophils and macrophages, such as those that can occur in infectious, inflammatory, or infiltrative disease processes.
Angiogenic Factors
Angiogenic factors not only are important in the development and progression of atherosclerosis, but they also seem to be involved in the pathogenesis of MI. Flt-1 is expressed on endothelial cells and macrophages, and binds not only to the vascular endothelial growth factor but also to PlGF, a platelet-derived protein. PlGF appears to promote the inflammatory process of atherosclerosis, which includes the recruitment of circulating macrophages and atherosclerotic intimal thickening. In patients with acute MI, PlGF is increased, regardless of cTn concentrations, implying that it is a biomarker of the atherothrombotic substrate, such as plaque instability, plaque disruption, or impending thrombosis ( Figure 8-e2 ). Soluble Flt-1 (sFlt-1), a type of Flt-1 without the transmembrane and intracellular tyrosine kinase domain, is a potential endogenous opponent of PlGF. sFlt-1 is believed to be able to capture PlGF and thereby reduce the amount available to bind to the receptor located on macrophages and endothelial cells.
Because both sFlt-1 and PlGF have also demonstrated changes in their blood concentrations during ongoing MI, they have a strong rationale as diagnostic tools. A multicenter study that enrolled patients who presented with symptoms suggestive of MI compared sFlt-1 and PlGF concentrations with the results of a fourth-generation cTnT assay and a high-sensitivity cTnT assay. For the diagnosis of MI, the combination of cTnT and sFlt-1 improved the performance of cTnT alone and led to a negative predictive value of 98.3% at time of presentation, but the combination of sFlt-1 and PlGF did not add diagnostic information when used together with high-sensitivity cTnT (area under the curve of 0.96 in both cases) (see Table 8-1 ). Because sensitive and high-sensitivity cTn assays have become the clinical standard in most countries, sFlt-1 and PlGF do not seem to have clinical relevance in the diagnosis of MI, despite a strong and independent association with long-term mortality. However, their association with plaque instability and coronary artery disease may render them helpful in the distinction of type I MI (plaque rupture) from type II MI (conditions with increased oxygen demand). This hypothesis is the subject of ongoing investigation.
Diagnostic Applications
The search for biomarkers of myocardial necrosis that are more sensitive or rise earlier than cTn has proven predominantly unsuccessful. In this author’s opinion, only one alternative biomarker, copeptin, has matured enough to currently justify possible routine clinical use for the early diagnosis of acute MI; therefore, it is discussed in greater detail.
Biomarkers Indicative of 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 ).
| Characteristics | AUC (95% CI) | AUC (95% CI) in Combination with hs-cTnT |
|---|---|---|
| hs-cTnT and hs-cTnI | 0.96 (0.94–0.98) | |
| c-TnT | 0.90 (0.86–0.94) | |
| Copeptin | 0.75 (0.69–0.81) | 0.96 (0.94–0.98) |
| Copeptin + c-TnT | 0.97 (0.95–0.98) | |
| h-FABP | 0.59 (0.48–0.70) | 0.88 (0.86–0.90) |
| sFIt-1 | 0.70 (0.64–0.76) | 0.96 (0.95–0.98) |
| PIGF | 0.60 (0.54–0.66) | 0.96 (0.95–0.98) |
| MPO | 0.63 (0.59–0.68) | 0.95 (0.92–0.97) |
| MRP8/14 | 0.65 (0.60–0.69) | 0.95 (0.92–0.97) |
| PAPP-A | 0.62 (0.57–0.67) | 0.95 (0.93–0.97) |
| CRP | 0.59 (0.54–0.64) | 0.95 (0.93–0.97) |
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