What Markers Will We Use and How Will We Use Them in ACS and Heart Failure Five Years From Now?
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.
- Wu AH, Jaffe AS. The clinical need for high-sensitivity cardiac troponin assays for acute coronary syndromes and the role for serial testing Am Heart J 2008; 155:208-214.
- Eggers KM, Oldgren J, Nordenskjold A, Lindahl B. Diagnostic value of serial measurement of cardiac markers in patients with chest pain: limited value of adding myoglobin to troponin I for exclusion of myocardial infarction. Am Heart J 2004;148:574-81.
- Wong GC, Morrow DA, Murphy S, et al. Elevations in troponin T and I are associated with abnormal tissue level perfusion: a TACTICS-TIMI 18 substudy. Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy-Thrombolysis in Myocardial Infarction. Circulation 2002;106:202-7.
- Jaffe AS, Eisenberg PR, Wilner GD. In vivo assessment of thrombosis and fibrinolysis during acute myocardial infarction In: Progress in Hematology, Elmer B. Brown, Editor, Grune & Stratton, Inc, 1988; 71-89.
- Breet NJ, van Werkum JW, Bouman HJ, et al. Comparison of Platelet Function Tests in Predicting Clinical Outcome in Patients Undergoing Coronary Stent Implantation. JAMA 2010; 303: 754 - 762.
- Lordkipanidzé M, Pharand C, Nguyen TA, Schampaert E, Palisaitis DA, Diodati JG.Comparison of four tests to assess inhibition of platelet function by clopidogrel in stable coronary artery disease patients Eur Heart J 2008; 29: 2877-2885.
- Hemker HC, Giesen P, AlDieri R, et al. The calibrated automated thrombogram (CAT): a universal routine test for hyper- and hypocoagulability. Pathophysiolol Haemost Thromb 2002; 32:249-253.
- Manasa J. Musabaike H. Masimirembwa C. Burke E. Luthy R. Mudzori J. Evaluation of the Partec flow cytometer against the BD FACSCalibur system for monitoring immune responses of human immunodeficiency virus-infected patients in Zimbabwe. Clin Vacc Immunol 2007; CVI. 14:293-8.
- Reichlin T. Hochholzer W. Stelzig C. Et al. Incremental value of copeptin for rapid rule out of acute myocardial infarction. J Am Col Cardiology 2009;. 54(1):60-8.
- Apple FS, Wu AHB, Mair J, et al. Future biomarkers for detection of ischemia and risk stratification in acute coronary syndrome. Clin Chem 2005; 51(5):810-24.
- Shih J. Datwyler SA. Hsu SC. Et al. Effect of collection tube type and preanalytical handling on myeloperoxidase concentrations. Clin Chem 2008; 54:1076-9.
- Ivandic BT. Spanuth E. Haase D. Lestin HG. Katus HA. Increased plasma concentrations of soluble CD40 ligand in acute coronary syndrome depend on in vitro platelet activation. Clin Chem 2007; 53:1231-4.
- Onoue K. Uemura S. Takeda Y. et al. Usefulness of soluble Fms-like tyrosine kinase-1 as a biomarker of acute severe heart failure in patients with acute myocardial infarction. Am J Cardiology 2009;104:1478-83.
- Lund J. Wittfooth S. Qin QP. Et al. Free vs total pregnancy-associated plasma protein A (PAPP-A) as a predictor of 1-year outcome in patients presenting with non-ST-elevation acute coronary syndrome. Clin Chem 2010; 56:1158-65.
- McConnell JP, Jaffe AS. Variability of lipoprotein-associated phospholipase A2 measurements. Clin Chem 2008; 54(5):932-933.
- Latini R. Masson S. Anand IS. et al. Prognostic value of very low plasma concentrations of troponin T in patients with stable chronic heart failure. Circulation 2007; 116:1242-9.
- Januzzi JL Jr. Bamberg F. Lee H. et al. High-sensitivity troponin T concentrations in acute chest pain patients evaluated with cardiac computed tomography. Circulation 2010; 121:1227-34.
- Peacock WF 4th. De Marco T. Fonarow GC. Et al. Cardiac troponin and outcome in acute heart failure. N Engl J Med 2008; 358:2117-26.
- Miller WL, Hartman KA, Burritt MF, Grill DE, Rodenheffer RJ, Burnett JC Jr, Jaffe AS. Serial biomarker measurements in ambulatory patients with chronic heart failure: the importance of change over time. Circulation 2007; 116:249-57.
- Hawkridge AM. Heublein DM. Bergen HR 3rd. Cataliotti A. Burnett JC Jr. Muddiman DC.Quantitative mass spectral evidence for the absence of circulating brain natriuretic peptide (BNP-32) in severe human heart failure. Proc Nat Acad Sciences 2005; 102:17442-7.
- Peleg A, Jaffe AS, Hasin Y. Enzyme-linked immunoabsorbent assay for detection of human serine protease corin in blood Clinica Chimica Acta 2009; 409:85-89.
- Giuliani I. Rieunier F. Larue C. et al. Assay for measurement of intact B-type natriuretic peptide prohormone in blood. Clin Chem 2006; 52:1054-61.
- Maisel A. Mueller C. Nowak R. et al. Mid-region pro-hormone markers for diagnosis and prognosis in acute dyspnea: results from the BACH (Biomarkers in Acute Heart Failure) trial. J Am Coll Cardiol 2010; 55:2062-76.
- Januzzi JL Jr. Peacock WF. Maisel AS. Et al. Measurement of the interleukin family member ST2 in patients with acute dyspnea: results from the PRIDE (Pro-Brain Natriuretic Peptide Investigation of Dyspnea in the Emergency Department) study. J Am Coll Cardiol 2007; 50:607-13.
- von Haehling KT,. Allhoff SPT, Cicoira T, et al. Prognostic utility of growth differentiation factor-15 in patients with chronic heart failure. J Am Coll Cardiol 2007;50:1054-60.
- Querejeta R, Varo N, Lopez B, et al. Serum carboxy-terminal propeptide of procollagen type I is a marker of myocardial fibrosis in hypertensive heart disease. Circulation 2000; 101:1729–1735.
- Timms PM, Mannan N, Hitman GA, et al. Circulating MMP9, vitamin D and variation in the TIMP-1 response with VDR genotype: mechanisms for inflammatory damage in chronic disorders? Q J Med 2002; 95:787–796.
- Fujimoto N. Onishi K. Sato A. et al. Incremental prognostic values of serum tenascin-C levels with blood B-type natriuretic peptide testing at discharge in patients with dilated cardiomyopathy and decompensated heart failure. J Card Fail 2009; 15:898-905.
- Lok DJ, Van Der Meer P, de la Porte PW, et al. Prognostic value of galectin-3, a novel marker of fibrosis, in patients with chronic heart failure: data from the DEAL-HF study. Clin Res Cardiol 2010; 99:323-8.
- Manzano-Fernandez S, Boronat-Garcia M, lbaladejo-Oton MD, et al. Complementary prognostic value of cystatin C, N-terminal pro-B-type natriuretic Peptide and cardiac troponin T in patients with acute heart failure. Am J Cardiol 2009; 103:1753-9.
- Damman K, van Veldhuisen DJ, Navis G, Voors AA, Hillege HL. Urinary neutrophil gelatinase associated lipocalin (NGAL), a marker of tubular damage, is increased in patients with chronic heart failure. Eur J Heart Fail 2008; 10:997-1000.
- Damman K, Van Veldhuisen DJ, Navis G, et al. Tubular damage in chronic systolic heart failure is associated with reduced survival independent of glomerular filtration rate. Heart 2010; 96:1297-302.
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