Serum S-100 Protein in Stroke and Cardiac Surgery
To the Editor:
We have followed with interest the discussion regarding S-100 proteins in stroke and cardiac surgery between Drs Wong and Bonser and Drs Missler and Wiesmann.
We noticed that Drs Missler and Wiesmann questioned the specificity of our Sangtec 100 LIA assay. It is correct that the validation of the Sangtec 100 LIA assay has yet to be published. A complete validation regarding specificity has, however, been performed at Sangtec Medical during development of the assay. The monoclonal antibodies used in the Sangtec 100 LIA assay are the same as in the Sangtec 100 IRMA assay, and they have been shown to be S-100B specific using the biosensor-based BIAcore system (L. Nyberg, A. Ullén, K. Haglid, E. Sandström, T. Stigbrand, and J. Brundell, unpublished data, 1998). In collaboration with DAKO, we have shown that recombinant human A1, A2, A4, and A6 are not detected in the Sangtec 100 LIA assay (see Figure⇓). Furthermore, calmodulin and troponin C are not measured in the Sangtec 100 LIA assay.
I hope that this information is valuable, and I agree with the authors that an assay for measuring cerebral damage must be S100B specific.
Several authors have shown that S-100 protein levels in serum are a quantitative marker of the extent of damage to the central nervous system (CNS).R1 R2 R3 R4 Therefore, use of this method has been proposed to detect possible cerebral injury after procedures such as coronary artery bypass.
The nomenclature used in studies of S-100 proteins has undergone some changes, which should be kept in mind to avoid possible misinterpretation of data. According to our present knowledge, the group of S-100 proteins now comprises 16 members, of which S-100A1 and S-100B are the most prominent and correspond to the previously used terms S100α (or alpha chain) and S100β (or beta chain). In the biologically active form, A1 and B form dimeric proteins, which had previously been named S-100a (formed by the monomeric proteins A1 and B), S-100b (B-B), and S-100a0 (A1-A1). The initial studies, which demonstrated the usefulness of S-100 in the diagnosis of CNS pathology, described the dimeric 21-kD protein S-100b to be specific for the CNS. However, the S-100B subunit has been found in several tissues outside the CNS, including heart and aorta.R5 R6
Most researchers have used two commercial assays produced by Byk Sangtec (Sangtec 100 IRMA, and Sangtec 100 LIA), which the company claims are strictly specific for S-100B, although the validation data has not yet been published. Martens et al,R7 who measured S-100 levels after cardiac arrest with the Sangtec 100 IRMA, state that the assay detects both the dimer B-B and A1-B.
In a letter, Wong and BonserR8 reported that they found high levels of S-100 in 10 patients who underwent coronary artery bypass grafting and 30 patients who underwent cardiothoracic surgery using cardiopulmonary bypass and cardiac arrest. None of the patients sustained a focal neurological deficit.
In an ongoing prospective study, we have measured S-100 blood levels in patients who underwent cardiothoracic surgery, using both the Sangtec 100 LIA and the assay described by us. The preliminary results after 20 patients demonstrate a high correlation between both assays (r=0.97, P≤0.001). However, all patients showed considerably elevated S-100 levels at the end of surgery (mean, 1.63±0.95 μg/L), although none of them suffered neurological deficits. Thus, our data were in accordance with the results of Wong and Bonser.R8 The S-100 levels we found exceeded those that we had measured in a group of patients suffering from major ischemic cerebral stroke (mean, 0.41±0.67 μg/L).R2
There are two possible explanations for these findings: (1) either both assays are not strictly specific for S-100B or (2) as suggested by the data presented by Dr Pisa, the measured levels of S-100 correspond to S-100B. In this case, it seems most probable, that the S-100B was released from tissue which had directly been damaged in the course of the surgery rather than from CNS tissue. If it holds true that the dimeric form S-100B-B is specific for CNS pathology, an assay is needed which specifically detects the dimeric protein S-100B-B rather than the subunit S-100B.
In either case, we feel that the measurement of S100 in serum with the methods that are actually available may not be clinically useful in the setting of cardiac or cardiothoracic surgery. Rather, research efforts should focus on markers that are strictly specific for the CNS, such as glial fibrillary acidic protein (GFAP). However, as shown in several studies, the measurement of S-100 can successfully be used in patients suffering from isolated CNS disorders.R1 R2 R3 R4 R9
Büttner T, Weyers S, Postert T, Sprengelmeyer R, Kuhn W. S-100 protein: serum marker of focal brain damage after ischemic territorial MCA infarction. Stroke.. 1997;28:1961–1965.
Missler U, Wiesmann M, Friedrich C, Kaps M. S-100 protein and neuron-specific enolase concentrations in blood as indicators of infarction volume and prognosis in acute ischemic stroke. Stroke.. 1997;28:1956–1960.
Abraha HD, Butterworth RJ, Bath PM, Wassif WS, Garthwaite J, Sherwood RA. Serum S-100 protein, relationship to clinical outcome in acute stroke. Ann Clin Biochem.. 1997;34:546–550.
Martens P, Raabe A, Johnsson P. Serum S-100 and neuron-specific encolase for prediction of regaining consciousness after global cerebral ischemia. Stroke.. 1998;29:363–2366.
Wong C, Bonser RS. Serum S-100 protein in stroke and cardiac surgery. Stroke.. 1998;29:2446. Letter.
- Copyright © 1999 by American Heart Association