What Biomarkers Are Useful for Detection of Myocardial Ischemia?

The presence of myocardial ischemia is, by definition, universal among patients with acute coronary syndrome (ACS). To support the clinical evaluation of such patients, biomarkers such as serum troponins are frequently tested. While conventional troponins (cTnI and cTnT) are an important foundation for detection of acute myocardial necrosis in the context of chest pain or other symptoms consistent with myocardial ischemia (and are the defining biomarker for the definition of acute myocardial infarction [AMI](1)), these biomarkers are limited by the fact that a substantial proportion of ACS patients have a negative cTn value at presentation, but then have subsequent cTn elevation on later blood draws. Furthermore, a substantial percentage of ACS patients have a cTn value that does not change, even after serial sampling over time. Such latter patients, by definition, do not have MI, but have unstable angina pectoris (UAP).

Thus, while outstanding diagnostic tools, cTnI and cTnT have limitations for ACS diagnosis; given the universal presence of myocardial ischemia as a cause of ACS, a biomarker reflective of ischemia, rather than necrosis per se, would theoretically be desirable, and incrementally useful to troponin testing. Such a biomarker of myocardial ischemia has been eagerly sought, but to date, no biochemical standard for detection of myocardial ischemia yet exists. Several candidates have recently been evaluated.

Highly Sensitive Troponin

Troponins are the gold standard for the diagnosis of acute MI, thus it is not intuitive to assume that they can be used to identify ischemia without frank myocardial necrosis. Nonetheless, a small percentage of the intracellular myocyte cTn is found in the cytosol, and this pool of cTn could theoretically be released by the heart in the absence of complete cardiomyocyte death. While such low-level releases of cTn may be undetectable by conventional assays, recent availability of highly sensitive troponin (hsTn) methods—which have the ability to detect very low concentrations of troponin with exceptionally high precision—has led to the recognition that many patients previously suspected as having UAP actually have measurable levels of hsTn.(2,3) Such patients will now be defined as AMI by recommended consensus guidelines.(1) However, recent studies have demonstrated that hsTn concentrations may be elevated in the absence of documented scarring on magnetic resonance imaging, may change during exercise testing(4) or may elevate following high heart rates induced with transvenous pacing in those without coronary artery disease(5); therefore, it is mechanistically reasonable to consider that hsTn may, in certain cases, reflect myocardial ischemia without irreversible cardiac injury. Whether this is the case remains to be proven conclusively.

Ischemia-Modified Albumin

It is hypothesized that deranged metabolic milieu present in ischemic organs leads to free radical modification of serum albumin as it passes through the oxygen-starved tissues, affecting its ability to bind cobalt at its amino-terminus. These modifications generate measurable amounts of “ischemia modified albumin” (IMA). An assay for detection of this abnormal albumin was developed, and has been evaluated as a tool to detect myocardial ischemia.

In pre-clinical studies a very rapid rise of IMA following induced myocardial ischemia was noted(6), and subsequent clinical studies in patients with chest discomfort a low IMA result appeared particularly promising for the confident exclusion of myocardial ischemia when combined with a normal cTn and 12-lead electrocardiogram.(7) Subsequent data have called the accuracy of IMA testing into question(3,8), and the value of the biomarker remains unclear, particularly given its non-specificity for myocardial ischemia.

B-type Natriuretic Peptide and N-terminal proBNP

B-type natriuretic peptide (BNP) and its amino-terminal pro-peptide equivalent (NT-proBNP) are important cardiac biomarkers widely-used for detection of heart failure (HF), and are well-established prognostic markers in ACS. Importantly, myocardial ischemia may also lead to an increased in ventricular wall stress resulting in release of BNP or NT-proBNP, as demonstrated in studies of exercise tolerance testing, although the extent of change was small.(9) Thus, off-label use of the natriuretic peptides as a diagnostic tool for ACS is also reasonable to consider. As demonstrated by Bhardwaj and colleagues(3), among patients with ACS, those with UAP (defined using a non-highly sensitive cTn assay) had higher concentrations of NT-proBNP than those with non-cardiac causes of chest symptoms; patients with AMI had the highest concentrations. Furthermore, the addition of NT-proBNP was additively useful to cTnT in reclassification analyses for the exclusion of ACS, such that those with low values for both biomarkers had an extremely low likelihood for ACS. A patient who was “double negative” for cTn and natriuretic peptide are thus at very low risk for adverse outcome, and have a very low likelihood for ACS.

Despite these results, the tight association between BNP or NT-proBNP and HF makes these markers less specific for myocardial ischemia, and in reclassification analyses, natriuretic peptides did not add to hsTn for the detection or exclusion of ACS. In addition, in another study of low risk patients, BNP was not useful for excluding ACS.(10) Thus, with more widespread use of hsTn, the value of natriuretic peptides for exclusion of myocardial ischemia may be less clear. This does not reduce the prognostic value of these markers in such patients, however.

Whole Blood Choline

Whole blood choline concentrations have potential promise for the diagnostic evaluation of patients with myocardial ischemia.(11,12) Concentrations of whole blood choline rise in patients with myocardial ischemia, even in settings where no detectable necrosis is present; the origin of choline generation resulting from myocardial ischemia is unclear, but a metabolic alteration within myocytes (from aerobic to anaerobic metabolism) is suspected. An important limitation of prior studies is that hsTn was not used; therefore, it is not clear how many of the patients detected by choline would have been identified using current generation hsTn assays. Large-scale validation of whole blood choline as a biomarker of myocardial ischemia is lacking, and analytical issues with its measurement remain.

Unesterified Free Fatty Acids

Blood plasma contains approximately 40 different forms of unesterified free fatty acid (FFAu) chains, and elevated FFAu have been associated with the presence of myocardial ischemia. The mechanism of FFAu release in the context of coronary ischemia is not yet understood; it is hypothesized that ischemia results in increased adipose lipolysis or acute changes in myocardial metabolism. FFAu levels rise rapidly after coronary angioplasty-induced ischemia(13), and two small studies suggested that FFAu may be sensitive clinical markers of coronary ischemia(14,15), elevating before traditional biomarkers of necrosis. More compellingly, a recently developed proprietary assay based on the fluorescent response of 7 FFAu probes had a 75% sensitivity, 72% specificity and a 92% negative predictive value for ACS in patients with chest pain(3); FFAu were equally useful to identify or exclude either UAP or acute MI.Interestingly, the results of testing for FFAu were additive to hsTn for detection of ACS. While the baseline FFAu value was important for diagnosis of ACS, a second measurement added significant information to the baseline value, implying serial sampling of FFAu may be of use in this context. Future analyses of this interesting biomarker class are justified.

Conclusions

To date, no biomarker has been shown to conclusively increase with ischemia alone. Of those that have been evaluated, hsTn and FFAu appear the most promising. Further studies will be necessary to better determine their utility in the assessment of the potential ACS patient.


References

  1. Thygesen K, Alpert JS, White HD, et al. Universal definition of myocardial infarction. Circulation. 2007;116:2634-53.
  2. 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.
  3. Bhardwaj A, Truong QA, Peacock F, et al. A mullti-center comparison of established and emerging cardiac biomarkers for the diagnostic evaluation of chest pain in the emergency department. Am Heart J. 2011;In Press.
  4. Sabatine MS, Morrow DA, de Lemos JA, Jarolim P, Braunwald E. Detection of acute changes in circulating troponin in the setting of transient stress test-induced myocardial ischaemia using an ultrasensitive assay: results from TIMI 35. Eur Heart J. 2009;30:162-9.
  5. Turer AT, Addo TA, Martin JL, et al. Myocardial ischemia induced by rapid atrial pacing causes troponin T release detectable by a highly sensitive assay insights from a coronary sinus sampling study. J Am Coll Cardiol. 2011;57:2398-405.
  6. Quiles J, Roy D, Gaze D, et al. Relation of ischemia-modified albumin (IMA) levels following elective angioplasty for stable angina pectoris to duration of balloon-induced myocardial ischemia. Am J Cardiol. 2003;92:322-4.
  7. Peacock F, Morris DL, Anwaruddin S, et al. Meta-analysis of ischemia-modified albumin to rule out acute coronary syndromes in the emergency department. Am Heart J. 2006;152:253-62.
  8. Kim JS, Hwang HJ, Ko YG, et al. Ischemia-modified albumin: is it a reliable diagnostic and prognostic marker for myocardial ischemia in real clinical practice? Cardiology. 2010;116:123-9.
  9. Sabatine MS, Morrow DA, de Lemos JA, et al. Acute changes in circulating natriuretic peptide levels in relation to myocardial ischemia. J Am Coll Cardiol. 2004;44:1988-95.
  10. Brown AM, Sease KL, Robey JL, Shofer FS, Hollander JE. The impact of B-type natriuretic peptide in addition to troponin I, creatine kinase-MB, and myoglobin on the risk stratification of emergency department chest pain patients with potential acute coronary syndrome. Ann Emerg Med. 2007;49:153-63.
  11. Body R, Griffith CA, Keevil B, et al. Choline for diagnosis and prognostication of acute coronary syndromes in the Emergency Department. Clin Chim Acta. 2009;404:89-94.
  12. Danne O, Lueders C, Storm C, Frei U, Mockel M. Whole blood choline and plasma choline in acute coronary syndromes: prognostic and pathophysiological implications. Clin Chim Acta. 2007;383:103-9.
  13. Kleinfeld AM, Prothro D, Brown DL, Davis RC, Richieri GV, DeMaria A. Increases in serum unbound free fatty acid levels following coronary angioplasty. Am J Cardiol. 1996;78:1350-4.
  14. Bhagavan NV, Ha JS, Park JH, et al. Utility of serum Fatty Acid concentrations as a marker for acute myocardial infarction and their potential role in the formation of ischemia-modified albumin: a pilot study. Clin Chem. 2009;55:1588-90.
  15. Apple FS, Kleinfeld AM, Adams JE. Unbound free fatty acid concentrations are increased in cardiac ischemia. Clin Proteomics. 2004;1:41-44.

Clinical Topics: Acute Coronary Syndromes, ACS and Cardiac Biomarkers

Keywords: Acute Coronary Syndrome, Angina, Unstable, Biological Markers, Myocardial Infarction, Troponin, Troponin I


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