As Yogi Berra has reminded us, it is always hard to make predictions, especially about the future. However, given the variety of biomarkers now being developed, there is a need to focus on those few that may be helpful.

Future Markers for ACS

For patients with ACS, in five year’s time we will understand how to use high sensitivity cardiac troponin (hscTn) assays and they will be the markers of choice. By that time, assays will be capable of detecting values in all patients and there will be sufficient precision to the assays that changes in values of significance will be simple to detect.¹ It is likely that a diagnosis of unstable coronary disease will require a rising pattern of cTn, assuming the timing is adequate to make that evaluation. It also is likely that a rising pattern even with values below the 99th% value will be considered abnormal once the assays develop sufficient sensitivity and precision to provide that information. Patients with normal cTn values, especially if very low, may be deemed not to have angina or structural heart disease at all, while those with elevations that are stable (i.e. without a changing pattern) will define the cohort with “stable” disease and thus “stable angina.” Again, if these values have increased over time, this diagnosis may be something that will be considered even if the absolute value is below the 99th%. Developing the criteria for these decisions will not come easily and will require seminal outcome studies. Once done, it is likely they will redefine how we classify patients with coronary artery disease.

Will other markers be necessary? They are not even now in my view² and that will be even less so in the future. However, there still may be a need for a marker to help define those individuals with elevated cTn who have unstable coronary artery disease as opposed to a non-ACS etiology (e.g. myocarditis, sepsis, etc). Such a marker might be a marker of pro-coagulant activity since most unstable coronary artery disease are likely to have increased activity either due to plaque rupture or a marked reduction in perfusion associated with various types of coronary flow limitations.³ Obviously, such a marker will not be specific for coronary artery disease, as there will be overlap in patients with other pro-coagulant disorders, such as pulmonary embolism. Thus, the intelligent use of such a marker will require clinical judgment. At present, there are no good assays to help in this area. Research assays are available for thrombin activity and thrombin generation such as fibrinopeptide A, a small amino acid cleaved from the central domain of fibrinogen in response to thrombin activity, F1.2, a fragment released when prothrombin is cleaved to its active substrate, thrombin, and thrombin-antithrombin 3 complexes (a combination of thrombin and antithrombin). These assays require fastidious sample handling, making them difficult to implement clinically.⁴ All of the machines used for platelet analysis, including platelet aggregation, attempt to mimic in vivo conditions in vitro. These are currently not very robust nor are they specific. ^5,6 There are ongoing efforts to develop novel thrombin assays⁷ as well as efforts to develop facile ways to evaluate platelets using flow cytometry that may eventually be done at bedside.⁸ Such techniques would markedly facilitate decision making about who might require angiography and/or coronary intervention.

Another area in which another marker might be needed is the very rapid exclusion of unstable coronary artery disease. Although ruling in AMI/ACS will occur in two hours for most patients using hscTn, there will be patients with delayed increases, such as might occur in the setting of ischemia behind total occlusions with poor collaterals. Given emergency departments wish to have a negative predictive accuracy of more than 99% before discharging patients, it is unlikely that one will be able to exclude AMI/ACS in 99% of patients within two hours. Thus, there will be a call for the use of non-specific stress markers such as copeptin (a stable precursor of vasopressin which is an acute phase reactant) to exclude acute disease.⁹ It is likely that this will only be relevant for a very small cohort of patients, but given such a small percentage of patients who present for evaluation have the real disease, this approach might have an attraction. It is also possible that by ascertaining specific protein fractions of cTn that a similar analysis may be achievable.

Finally, the holy grail of biomarkers would be to develop an assay that can predict plaque rupture occurring in the near future. There are many candidates such as myleoperoxidase, soluble CD 40 ligand, placental growth factor (PLGF), pregnancy associated plasma protein A (PAPP-A), and lipoprotein associated phospholipase A2 (LpPLA2).¹⁰ All have received more hype than the data deserve and substantial pre-analytical and analytical challenges need to be overcome, an area which clinicians often ignore but which is crucial for accurate, reproducible assays.^11-15 PAPP-A is at present the most attractive of these markers. Time will tell if markers can do this and/or if the underlying hypothesis is even correct.

Future Markers for Congestive Heart Failure

For heart failure hscTn will also have a role. Structural abnormalities will often be marked by changes in baseline values, allowing identification of patients long before the overt onset of symptoms, during what might be considered the very early phase of heart failure. ^16,17 It is likely that most if not all patients with diagnosed heart failure will be monitored with serial values, since even transient elevations appear to be highly prognostic both in the acute¹⁸ and chronic setting.¹⁹ At present, it is unclear how often to sample hscTn to achieve this goal, but with indwelling catheter based systems, such monitoring may become more facile. With time, it may be that we will respond to changes in values with preventative measures.

The need for additional markers will be more robust in this area. Some interrogation of the neurohormonal system will be helpful but what marker is unclear. It may turn out that when we understand the determinants of the natriuretic peptide system we will be able to measure analytes that will provide even more informative than BNP and NTproBNP. For example, it may be that measuring the active moiety peptide (BNP 1-32), which makes up a tiny fraction of the BNP measured by present day assays²⁰ will be helpful. Or perhaps measuring the convertases (corin for which there is an assay²¹ and furin for which one is being developed) that cleave proBNP (for which there also is an assay²²) to its active moiety may be helpful diagnostically and prognostically, as it is clear that there is inadequate processing of natriuretic peptides in patients with heart failure. There will also be assays such as MR-ANP as well as others from a long list of other analytes that will compete with these.²³

There are two other areas where testing will help. Although natriuretic peptides are highly prognostic they are not as prognostic as so- called “death markers.” There are currently three contenders: Proadrenomellulin (proADM),²³ ST2, a decoy receptor for IL-33,²⁴ and growth differentiation factor – 15 (GDF-15), a member of the transforming growth factor-β cytokine superfamily and a macrophage-inhibitory cytokine 1.²⁵ All have been shown to be more predictive of mortality than natriuretic peptide levels because they identify risk in patients who have dyspnea whether or not it is heart failure mediated. One of these may survive to clinical use.

In addition, a large number of markers related to interstitial or so called extracellular matrix cardiac processes are being developed. These will help substantially with the evaluation of diastolic dysfunction and remodeling. None of these markers, which include procollagen peptides I and III²⁶ a large number of matrix metalloproteinases (MMPs) and their inhibitors (TIMPS),²⁷ tenascin C, an extracellular matrix glycoprotein²⁸ or galectin 3, a member of the β-galactoside-binding animal lectin family which interacts with a large number of matrix proteins²⁹ has caught on as yet. It is likely that at least one will be helpful.

Finally, markers of renal dysfunction such as cystatin C³⁰ will be extremely helpful in evaluating kidney function. Markers such as NGAL (neutrophil gelatinase associated lipocalin) which is released by macrophages in response to renal tubular damage,³¹ and kidney injury molecule 1 (KIM 1), also a marker of tubular damage,³² will be useful in detecting acute kidney injury, commonly present in heart failure patients and associated with substantial risk. These or similar markers are also likely to allow earlier diagnosis of cardiorenal syndrome, and potentially early initiation of new therapies may be beneficial.

Many of these assays are close to being ready for clinical use, so in some ways the future is now. However, many efforts have been thwarted by inadequate sample preparation and a lack of attention to analytic detail. Clinicians must become more sensitive to these issues. Once this testing is available, it will be up to us to evaluate how to use it and to refine treatment algorithms based on them.

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Keywords: Dyspnea, Fibrinopeptide A, Pulmonary Embolism, Thrombin, Troponin, Vasopressins, Transforming Growth Factors, Tenascin, Natriuretic Peptide, Brain, Galectin 3, Furin, Lipocalins, Angina, Stable

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