Absence of auto-antibodies against cardiac troponin I predicts improvement of left ventricular function after acute myocardial infarction

Leuschner, Florian; Li, Jin; Göser, Stefan; Reinhardt, Lars; Öttl, Renate; Bride, Peter; Zehelein, Joerg; Pfitzer, Gabriele; Remppis, Andrew; Giannitsis, Evangelos; Katus, Hugo A.; Kaya, Ziya

doi:10.1093/eurheartj/ehn268

Cited by 96 publications

(118 citation statements)

References 24 publications

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“…In general, autoantibodies which form macroanalyte complexes are not believed to be disease-causing although cases associated with autoimmune disorders have been described [16,17] and reports suggesting an association between the presence of autoantibodies against cTnI and cardiomyopathy have been published [18][19][20]. Based on current evidence, the main problem caused by a circulating macroanalyte is that it leads to multiple, possibly invasive, investigations in search of a cause.…”

Section: Introductionmentioning

confidence: 99%

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High incidence of macrotroponin I with a high-sensitivity troponin I assay

Warner

Marshall

2016

Clinical Chemistry and Laboratory Medicine (CCLM)

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Background:Cardiac troponin is the preferred biomarker of myocardial injury. High-sensitivity troponin assays allow measurement of very low levels of troponin with excellent precision. After the introduction of a high-sensitivity troponin I assay the laboratory began to receive enquiries from clinicians about clinically discordant elevated troponin I results. This led to a systematic investigation and characterisation of the cause.Methods:Routine clinical samples were measured by the Architect High Sensitive Troponin-I (hsTnI) and the VITROS Troponin I ES assays (VitrosTnI). Results that were elevated according to the Architect but not the VITROS assay (Group 1) or results elevated by both assays but disproportionately higher on the Architect (Group 2) were re-analysed for hsTnI after re-centrifugation, multiple dilutions, incubation with heterophilic blocking reagents, polyethylene glycol (PEG) precipitation, and Protein A/G/L treatment. Sephacryl S-300 HR gel filtration chromatography (GFC) was performed on selected specimens.Results:A high molecular weight complex containing immunoreactive troponin I and immunoglobulin (macrotroponin I) was identified in 5% of patients with elevated hsTnI. Patients with both macrotroponin and myocardial injury had higher and longer elevation of hsTnI compared with VitrosTnI with peaks of both macrotroponin and free troponin I-C complex on GFC.Conclusions:Circulating macrotroponin I (macroTnI) causes elevated hsTnI results with the Architect High Sensitive Troponin-I assay with the potential to be clinically misleading. The assay involved in this investigation may not be the only assay affected by macrotroponin. It is important for laboratories and clinicians to be aware of and develop processes to identify and manage specimens with elevated results due to macrotroponin.

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Section: Introductionmentioning

confidence: 99%

“…Circulating troponin autoantibodies are not rare, having been identified in 2%-20% of individuals, with or without cardiac disease, in various studies [20][21][22][23][24]. They may be directed towards cTnI [19,22] or cardiac troponin T [20,21].…”

Section: Introductionmentioning

confidence: 99%

High incidence of macrotroponin I with a high-sensitivity troponin I assay

Warner

Marshall

2016

Clinical Chemistry and Laboratory Medicine (CCLM)

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“…Recent work from our laboratory and others has focused on the dysregulation of the immune system as an essential modulator of disease induction and progression in heart failure (1,2). In this context, release of cardiac troponin I (TnI) from damaged cardiomyocytes into the circulation is believed to trigger an autoimmune response to TnI (3,4).…”

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confidence: 99%

Critical role of RAGE and HMGB1 in inflammatory heart disease

Bangert

Andrassy

Müller

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

130

111

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Autoimmune response to cardiac troponin I (TnI) induces inflammation and fibrosis in the myocardium. High-mobility group box 1 (HMGB1) is a multifunctional protein that exerts proinflammatory activity by mainly binding to receptor for advanced glycation end products (RAGE). The involvement of the HMGB1-RAGE axis in the pathogenesis of inflammatory cardiomyopathy is yet not fully understood. Using the well-established model of TnI-induced experimental autoimmune myocarditis (EAM), we demonstrated that both local and systemic HMGB1 protein expression was elevated in wild-type (wt) mice after TnI immunization. Additionally, pharmacological inhibition of HMGB1 using glycyrrhizin or anti-HMGB1 antibody reduced inflammation in hearts of TnI-immunized wt mice. Furthermore, RAGE knockout (RAGE-ko) mice immunized with TnI showed no structural or physiological signs of cardiac impairment. Moreover, cardiac overexpression of HMGB1 using adeno-associated virus (AAV) vectors induced inflammation in the hearts of both wt and RAGE-ko mice. Finally, patients with myocarditis displayed increased local and systemic HMGB1 and soluble RAGE (sRAGE) expression. Together, our study highlights that HMGB1 and its main receptor, RAGE, appear to be crucial factors in the pathogenesis of TnI-induced EAM, because inhibition of HMGB1 and ablation of RAGE suppressed inflammation in the heart. Moreover, the proinflammatory effect of HMGB1 is not necessarily dependent on RAGE only. Other receptors of HMGB1 such as Toll-like receptors (TLRs) may also be involved in disease pathogenesis. These findings could be confirmed by the clinical relevance of HMGB1 and sRAGE. Therefore, blockage of one of these molecules might represent a novel therapeutic strategy in the treatment of autoimmune myocarditis and inflammatory cardiomyopathy. myocarditis | cytokines | AAV

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“…Most studies assessed anti-troponin I antibodies (9,12,14,(39)(40)(41)(42)(45)(46)(47)(48)50,51,(53)(54)(55)(56)(57)(58), whereas anti-troponin T antibodies were assessed in only 16% (n=1,636) of individuals (11,43,44,49,52) (including 993 individuals where both types of autoantibodies were evaluated) (11,44,49).…”

Section: Resultsmentioning

confidence: 99%

“…For instance, conflicting data have been published concerning the impact on prognosis in heart disease (4). Leuschner et al showed that the absence of autoantibodies against cardiac troponin I predicted an improvement of left ventricular function after an acute myocardial infarction (MI) (11). Doesch et al, however, described a beneficial effect of anti-troponin I autoantibodies in the setting of DCM (improved survival), but not in patients with ICM (12).…”

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confidence: 99%

Anti-cardiac troponin antibodies in clinical human disease: a systematic review

Vilela¹,

Bettencourt‐Silva²,

Costa³

et al. 2017

Ann. Transl. Med.

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Anti-cardiac troponin antibodies have been studied in different types of clinical diseases and in healthy populations. A systematic review of published data on anti-troponin antibodies was carried out (search performed on PubMed, ISI Web of Knowledge and Scopus databases). From title and abstract analysis, thirty-three articles were included that met the pre-specified criteria; after full-text analysis, nine articles were excluded. Most studies assessed anti-troponin I antibodies. The prevalence of anti-cardiac troponin antibodies in healthy individuals ranged from 0.0% to 20.0%. The prevalence of anti-troponin I autoantibodies in dilated cardiomyopathy (DCM) ranged from 7.0% to 22.2%. Other conditions under study were myocardial infarction, ischemic cardiomyopathy (ICM), peripartum cardiomyopathy (PPCM), Chagas disease, Emery-Dreifuss muscular dystrophy (EDMD) and renal transplantation. In the different patient populations studied, anti-cardiac troponin antibodies have been shown to be either positively or negatively associated with prognostic and clinical features. In what concerns a possible value as biomarkers, these assays have not emerged up to the present moment as important aids for practical clinical decisions in cardiac or other types of patients. In what concerns pathophysiology, anti-cardiac troponin autoantibodies may play a role in different diseases. It can be speculated that these antibodies could be involved in perpetuating some degree of cardiac injury after an event, such as myocardial infarction or PPCM. The major function of the heart is its contractile function, and cardiac muscle contains sarcomeres, which include different types of molecules, of which actin and myosin are essential for strength generation during contraction. Other molecules, such as cardiac troponins, play a role of regulation concerning cardiac muscle contraction. Cardiac troponins I and T have been shown to be different molecules than the corresponding ones in skeletal muscle, and have gained importance as cardiac biomarkers (1,2).Research has shown that antibodies against cardiac troponins exist in different settings, and questions about their role in the cardiovascular pathological continuum have emerged over the last years. The possible role of cardiac troponin autoantibodies in disease processes [and particularly in dilated cardiomyopathy (DCM) and ischemic cardiomyopathy (ICM)] has gained interest (3-6).Animal models in mice have demonstrated that anticardiac troponin I autoantibodies are capable of inducing heart dilatation and dysfunction, apparently through interactions with the calcium balance in cardiomyocytes (7). Okazaki et al. showed that in mice antibodies to cardiac troponin I stained the surface of cardiomyocytes, implying the presence of troponin I on the cell surface (differing from cardiac troponin T) (7). Göser et al. immunized mice with cardiac troponin I, leading to severe inflammation of the myocardium, cardiomegaly, fibrosis and 30% mortality over 270 days (8). However, in a study carri...

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Absence of auto-antibodies against cardiac troponin I predicts improvement of left ventricular function after acute myocardial infarction

Abstract: We demonstrate for the first time that the prevalence of cTnI-Abs in patients with AMI has an impact on the improvement of the LVEF over a study period of 6-9 months.

Cited by 96 publications

References 24 publications

High incidence of macrotroponin I with a high-sensitivity troponin I assay

High incidence of macrotroponin I with a high-sensitivity troponin I assay

Critical role of RAGE and HMGB1 in inflammatory heart disease

Anti-cardiac troponin antibodies in clinical human disease: a systematic review

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