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Diagnostic and prognostic validity of different biomarkers in patients with suspected myocarditis

Myocarditis is a highly variable disease ranging from oligosymptomatic courses with palpitations over acute coronary syndrome-like presentations to cardiac arrhythmias, chest pain, and acute or chronic heart failure. The diagnosis of myocarditis based on clinical symptoms alone is unreliable and usually needs confirmation by laboratory testing, ECG, cardiac imaging, heart catheterization and, importantly, the analysis of endomyocardial biopsies (EMB) which is the gold standard for diagnosing myocarditis. Histological and immunohistological analyses as well as molecular biological detection of microbial gene signatures in the myocardium are decisive for evaluating the adequate treatment of the patients.

Some cardiac biomarkers which are currently used to detect myocyte injury such as cardiac troponins, volume overload (natriuretic peptides), acute endogenous stress (Copeptin), and acute heart failure with microcirculatory dysfunction (MR-proADM) have contributed to improve diagnosis and risk stratification in acute coronary syndromes and chronic heart failure. The objective of this study was to validate the diagnostic performance of these biomarkers in patients with suspected myocarditis undergoing EMB.
Myocardial Disease

In this study 70 patients with clinical suspected myocarditis were enrolled presenting at least one of the following features not related to myocardial ischemia: impaired global or regional left ventricular systolic function, pericardial effusion, or sustained or non-sustained ventricular tachycardia or ventricular fibrillation of unknown origin. The mean time between hospital admission and biopsy was 2.9 ± 1.9 days. The biopsy sample sites [right (n = 8) vs. left ventricle (n = 62), wall segment] were chosen according to the findings of echocardiography or magnetic resonance imaging (MRI) of the heart, if available (33 patients with MRI before EMB). Blood samples for determination of biomarkers were collected on the day of EMB.

Immunohistochemical analyses of the EMB revealed acute myocarditis (AM) in 6, chronic myocarditis (CM) in 36 and no myocardial inflammation (NM) in 28 patients. Patients with AM tended to have a better left ventricular ejection fraction (LVEF) compared to other groups (p = 0.068). In 16 patients with a LVEF >45 %, additional biopsy indications as signs of myocardial inflammation in MRI (n = 11), ventricular tachyarrhythmias (n = 3), complete atrioventricular block (n = 1), and pericardial effusion (n = 1) were observed.

Hs-TnT was significantly increased in acute myocarditis (AM) compared to those without myocardial inflammation (Fig. 1). In addition, the concentration of creatinine kinase (CK) tended to be higher in AM (p = 0.057). Concentration of NT-proBNP, MR-proADM, Copeptin, or Cystatin C glomerular filtration rate did not significantly differ between groups.

In patients with myocarditis and presence of viral genomes in the myocardium (parvovirus B19 n = 9; parvovirus B19 and HHV-6 n = 1; Epstein-Barr virus n = 1; Epstein-Barr virus and HHV-6 n = 1), hs-TnT [37.4 (21.9–163.6) pg/ml] was increased compared to those with myocarditis without evidence of viral genomes [20.0 (14–44.4) pg/ml; p = 0.042] or those without myocardial  inflammation [19.5 (13.8–50.7) pg/ml; p = 0.021]. Concentrations of the other investigated biomarkers were not significantly different with respect to the prevalence of cardiac inflammation and/or viral genomes. In patients without myocardial inflammation, viral genome was detected in 5 subjects (18 %). These patients with viral latency did not differ from those without presence of cardiac viral genomes concerning baseline characteristics or biomarkers concentrations.

Regarding the duration of symptoms patients with a longer period symptoms (≥14 days) had a worse EF (34.4 ± 17.1 % vs.47.3 ± 17.3 %; p = 0.014) and a lower systolic blood pressure (112.1 ± 21.7 vs. 126.8 ± 28.4 mmHg; p =0.047) compared to those with shorter onset of symptoms (<14 days). Patients with a shorter history of symptoms had higher concentrations of hs-TnT, whereas those with longer standing symptoms had higher concentrations of MRproADM and NT-proBNP.

Concerning the outcome during the first 12 months after EMB, 8 primary endpoints occurred: 6 patients died from cardiac cause and 2 patients underwent cardiac transplantation. Regarding the predictive value of the biomarkers for outcome only NT-proBNP concentration above the 4th quartile (≥4,245 pg/ml) proved to be of prognostic relevance for the occurrence of cardiac death or heart transplantation (p = 0.002).


After exclusion of other common causes of troponin elevations (e.g. coronary artery disease, tachyarrhythmia, hypertensive crisis, cardiac decompensation) an elevated hs-Troponin T ([50 pg/ml) is highly predictive for the diagnosis of acute myocarditis. As in other cardiac dysfunction states NT-proBNP is a valuable prognostic marker in patients with clinically suspected myocarditis. Newer cardiac biomarkers like MR-proADM or Copeptin do not confer additional information for the diagnosis or prognosis of (viral) myocarditis.
In the present study Ukena et al. demonstrated that hs-Troponin T ([50 pg/ml) but not Copeptin and MR-proADM is a predictive marker for the diagnosis of acute myocarditis. Limitations of the study are given by the fact that this small, single-centre study may be underpowered concerning the prognostic value. The limited study size and the low number of events may—in part—account for the lack of prognostic utility of the novel biomarker MR-proADM. Another limitation is the rather low number of subjects with acute myocarditis compared to chronic myocarditis cases which hampers the generalizability of the results and requires further large scale studies. Additionally, measurements of biomarkers in addition to the results of EMB during follow-up periods are required to identify patients with ongoing myocarditis.


Authors: Ukena C, Kindermann M, Mahfoud F, Geisel J, Lepper PM, Kandolf R, Böhm M, Kindermann I. Clin Res Cardiol. 2014 Apr 30. [Epub ahead of print]

Notes to editor

Presented by: Karin Klingel, Department of Molecular Pathology, University Hospital Tübingen, Germany
The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.

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